Crystalline solid and amorphous forms of (−)-halofenate and methods related thereto

ABSTRACT

The present invention provides crystalline solid and amorphous forms of (−)-halofenate. The crystalline solid forms may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of conditions associated with blood lipid deposition in a mammal, particularly those diseases related to Type 2 diabetes and hyperlipidemia. The invention also relates to a method for preventing or treating Type 2 diabetes and hyperlipidemia in a mammal comprising the step of administering a therapeutically effective amount of crystalline solid and amorphous forms of (−)-halofenate.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.13/938,548, filed Jul. 10, 2013, which is a continuation of U.S.application Ser. No. 13/470,142, filed May 11, 2012 which was granted onJul. 10, 2013, which is a continuation of U.S. application Ser. No.11/408,609, filed Apr. 20, 2006, which claims the benefit of U.S. PatentApplication Ser. No. 60/673,655, filed Apr. 20, 2005, the content ofwhich is incorporated herein by reference herein, all of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to crystalline solid and amorphous formsof the title compound which has the chemical structure shown below:

2-acetamidoethyl 4-chlorophenyl-(3-trifluoromethylphenoxy)-acetate,(3-trifluoromethylphenoxy)-(4-chlorophenyl)acetic acid2-acetylaminoethyl ester or halofenate is a chiral compound which isuseful in ameliorating Type II diabetes and hyperlipidemia (see, forexample, U.S. Pat. No. 6,262,118 and U.S. patent application Ser. No.10/656,567, which are incorporated by reference in their entirety).Halofenate contains a single chiral center at an asymmetricallysubstituted carbon atom alpha to one of the carbonyl carbon atoms (*),and therefore exists in two enantiomeric forms.

Significant side effects have been noted using racemic halofenateincluding gastrointestinal bleeding from stomach and peptic ulcers (see,e.g., Friedberg, S. J. et al., Clin. Res. (1986) Vol. 34, No. 2:682A).In addition, there were some indications of drug-drug interactions ofracemic halofenate with agents such as warfarin sulfate (also referredto as 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin or COUMADIN™ (DupontPharmaceuticals, E.I. Dupont de Nemours and Co., Inc., Wilmington, Del.U.S.A.)) (see, e.g., Vesell, E. S. and Passantanti, G. T., Fed. Proc.(1972) 31(2): 538). COUMADIN™ is believed to be stereospecificallymetabolized by cytochrome P450 2C9, the principal form of human liverP450 which modulates in vivo drug metabolism of several other drugs(see, e.g., Miners, J. O. et al, Bri. J. Clin. Pharmacol. (1998) 45:525-538). Cytochrome P450 2C9 is inhibited by racemicα-(phenoxy)phenylacetic acid, e.g., halofenic acid. Thus, administrationof a racemic halofenate can lead to a variety of drug interactionproblems with other drugs, including anticoagulants, anti-inflammatoryagents and other drugs that are metabolized by cytochrome P450 2C9.

It has been found that the (−)-enantiomer of halofenic acid is abouttwenty-fold less active in its ability to inhibit cytochrome P450 2C9compared to the (+)-enantiomer (see, for example, U.S. Pat. No.6,262,118). Thus, it is desirable to administer the (−)-enantiomer ofhalofenic acid or its derivatives which are substantially free of the(+)-enantiomer to reduce the possibility of drug interactions.

While biological activity is a sine non qua for an effective drug, acompound must also be capable of large scale manufacturing and thephysical properties of the compound can markedly impact theeffectiveness and cost of a formulated active ingredient.

Amorphous and different crystalline solid forms of compounds arefrequently encountered among pharmaceutically useful compounds. Physicalproperties including solubility, melting point/endotherm maximum,density, hardness, crystalline shape and stability can be quitedifferent for different forms of the same chemical compound.

Crystalline solid and amorphous forms may be characterized by scatteringtechniques, e.g., x-ray diffraction powder pattern, by spectroscopicmethods, e.g., infra-red, solid state ¹³C and ¹⁹F nuclear magneticresonance spectroscopy and by thermal techniques, e.g., differentialscanning calorimetry or differential thermal analysis. Although theintensities of peaks in the x-ray powder diffraction patterns ofdifferent batches of a compound may vary slightly, the peaks and thepeak locations are characteristic for a specific crystalline solid oramorphous form. Additionally, infrared, Raman and thermal methods havebeen used to analyze and characterize crystalline and solid amorphousforms. Solid and amorphous forms may be characterized by data from theX-ray powder diffraction pattern determined in accordance withprocedures which are known in the art (see J. Haleblian, J. Pharm. Sci.1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 196958:911-929).

There is a problem identifying a suitable form which (i) possessesadequate chemical stability during the manufacturing process, (ii) isefficiently prepared, purified and recovered, (ii) provides acceptablesolubility in pharmaceutically acceptable solvents, (iii) is amenable tomanipulation (e.g. flowability and particle size) and formulation withnegligible decomposition or change of the physical and chemicalcharacteristics of the compound, (iv) exhibits acceptable chemicalstability in the formulation. In addition, forms containing a high molarpercent of the active ingredient are highly desirable since theyminimize the quantity of material which must be formulated andadministered to produce a therapeutically effective dose. These oftenconflicting requirements make identification of suitable forms achallenging and important problem which must be solved by the skilledpharmaceutical scientist before drug development can proceed in earnest.

Therefore, there is a need for crystalline solid and amorphous forms of(−)-halofenate and an efficient process for producing crystalline solidforms of (−)-halofenate. Solutions to the above difficulties anddeficiencies are needed before halofenate becomes effective for routinetreatment of insulin resistance, Type 2 diabetes and hyperlipidemia.

Biphenyl compounds are generally crystalline, poorly water soluble andhydrophobic, resulting in difficulties in the preparation ofpharmaceutical formulations and problems associated withbioavailability. Accordingly, efforts were made to discover amorphousand crystalline solid forms of (−)-halofenate and to investigate theproperties thereof. There were discovered five crystalline solid formsand an amorphous form. The present invention fulfills the above needs byproviding amorphous and crystalline solid forms of (−)-halofenate andmethods for alleviating insulin resistance, Type 2 diabetes andhyperlipidemia, while presenting a better adverse effect profile.

BRIEF SUMMARY OF THE INVENTION

The invention provides the compound of formula (I):

in substantially pure crystalline solid or amorphous forms.

In one embodiment, the present invention relates to“(−)-2-acetamidoethyl4-chlorophenyl-(3-trifluoromethylphenoxy)-acetate”,“(3-trifluoromethylphenoxy)-(4-chlorophenyl)acetic acid2-acetylaminoethyl ester” or “(−)-halofenate”, in a crystalline solidform, which for purposes of this invention are identified as Forms A, B,C, D and E. Forms A through E are anhydrous. In another embodiment, thepresent invention relates to (−)-halofenate in a substantially pureamorphous form.

Within each of the above embodiments, the present invention provideseach of the crystalline forms and the amorphous form in a substantiallypure form.

In another aspect, the present invention provides a method of preparing(−)-halofenate in a crystalline solid form A, including substantiallypure forms, comprising at least one of:

(i) heating (−)-halofenate in at least one solvent selected from thegroup consisting of heptane, 2-propanol, and combinations thereof;crystallizing at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent;(ii) drying a crystal of crystalline solid form B of (−)-halofenate;(iii) drying a crystal of crystalline solid form C of (−)-halofenate;(iv) heating (−)-halofenate in at least one solvent selected from thegroup consisting of heptane, 2-propanol, and combinations thereof;crystallizing in the presence of a crystal of a solid form of(−)-halofenate at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent; and(v) crystallizing (−)-halofenate from at least one solvent selected fromthe group consisting of acetonitrile, benzene, cyclohexanol, t-butylmethyl ether and combinations thereof and drying.

In another aspect, the present invention provides a method of preparing(−)-halofenate in a solid form B, including a substantially purecrystalline solid form B, comprising crystallizing (−)-halofenate fromat least one solvent selected from the group consisting of heptane,2-propanol, and combinations thereof and at a temperature of from about20° C. to −10° C. and drying until the crystals contain from about 2% toabout 3% solvent.

In another aspect, the present invention provides a method of preparing(−)-halofenate in a crystalline solid form C, including a substantiallypure crystalline solid form C, comprising crystallizing (−)-halofenatefrom at least one solvent selected from the group consisting of heptane,2-propanol, and combinations thereof and at a temperature of from about20° C. to −10° C. and drying until the crystals contain about 0.05% toabout 0.3% solvent.

In another aspect, the present invention provides a method of preparing(−)-halofenate in a crystalline solid form D, including substantiallypure crystalline solid form D, comprising crystallizing (−)-halofenatefrom at least one solvent selected from the group consisting ofacetonitrile, benzene, cyclohexanol, t-butyl methyl ether, methanol,water and combinations thereof and drying.

In another aspect, the present invention provides a method of preparing(−)-halofenate in a crystalline solid form E, including substantiallypure crystalline solid form E, comprising crystallizing (−)-halofenatefrom t-butyl methyl ether and heptane and drying.

In another aspect, the present invention provides a method of preparing(−)-halofenate in an amorphous form, including substantially pureamorphous form, comprising heating (−)-halofenate at high humidity.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of (−)-halofenate containing in a substantially pureform selected from the group consisting of crystalline solid form A, B,C, D, E and amorphous.

In another aspect, the invention provides methods for preventing ortreating/modulating Type 2 diabetes in a mammal containing atherapeutically effective amount of an (−)-halofenate in a substantiallypure form selected from the group consisting of crystalline solid formA, B, C, D, E and amorphous and a pharmaceutically acceptable carrier.The present invention further provides methods for modulating insulinresistance and alleviating hyperlipidemia in a mammal comprisingadministering to the mammal a therapeutically effective amount of(−)-halofenate in a substantially pure form selected from the groupconsisting of crystalline solid form A, B, C, D, E and amorphous.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: XRPD pattern of crystalline solid form A of (−)-halofenate.

FIG. 2: XRPD peak listing for crystalline solid form A of(−)-halofenate.

FIG. 3: FT-infra red spectrum of crystalline solid form A of(−)-halofenate.

FIG. 4: FT-infra red spectrum with labeled peaks of crystalline solidform A of (−)-halofenate.

FIG. 5: FT-Raman spectrum of crystalline solid form A of (−)-halofenate.

FIG. 6: FT-Raman spectrum with labeled peaks of crystalline solid form Aof (−)-halofenate.

FIG. 7: Cyclic DSC analysis of crystalline solid form A of(−)-halofenate.

FIG. 8: Hot stage microscopy of crystalline solid form A of(−)-halofenate.

FIG. 9: Light microscopy of crystalline solid form A of (−)-halofenateafter cyclic DSC.

FIG. 10: Thermal analysis of crystalline solid form A of (−)-halofenate.

FIG. 11: Automated moisture sorption/desorption data of crystallinesolid form A of (−)-halofenate.

FIG. 12: ¹H NMR spectrum of crystalline solid form A, D and E of(−)-halofenate.

FIG. 13: XRPD pattern of crystalline solid form B of (−)-halofenate.

FIG. 14: XRPD peak listing for crystalline solid form B of(−)-halofenate.

FIG. 15: DSC analysis of crystalline solid form B of (−)-halofenate.

FIG. 16: XRPD pattern of crystalline solid form C of (−)-halofenate.

FIG. 17: DSC analysis of crystalline solid form C of (−)-halofenate.

FIG. 18: XRPD pattern of crystalline solid form D of (−)-halofenate.

FIG. 19: XRPD peak listing for crystalline solid form D of(−)-halofenate.

FIG. 20: FT-infra red spectrum of crystalline solid form D of(−)-halofenate.

FIG. 21: FT-infra red spectrum with labeled peaks of crystalline solidform D of (−)-halofenate.

FIG. 22: FT-Raman spectrum of crystalline solid form D of(−)-halofenate.

FIG. 23: FT-Raman spectrum with labeled peaks of crystalline solid formD of (−)-halofenate.

FIG. 24: Thermal analysis of crystalline solid form D of (−)-halofenate.

FIG. 25: Automatic moisture sorption/desorption data of crystallinesolid form D of (−)-halofenate.

FIG. 26: XRPD pattern of crystalline solid form E of (−)-halofenate.

FIG. 27: XRPD peak listing of crystalline solid form E of(−)-halofenate.

FIG. 28: FT-infra red spectrum of crystalline solid form E of(−)-halofenate.

FIG. 29: FT-infra red spectrum with peak listing of crystalline solidform E of (−)-halofenate.

FIG. 30: FT-Raman spectrum of crystalline solid form E of(−)-halofenate.

FIG. 31: FT-Raman spectrum with peak listing of crystalline solid form Eof (−)-halofenate.

FIG. 32: Thermal analysis of crystalline solid form E of (−)-halofenate.

FIG. 33: Hot stage microscopy of crystalline solid form E of(−)-halofenate.

FIG. 34: Automated moisture sorption/desorption analysis of crystallinesolid form E of (−)-halofenate.

FIG. 35: XRPD of amorphous form of (−)-halofenate.

FIG. 36: Approximate solubility of (−)-halofenate in solvents at RT andat 50° C.

FIG. 37: Summary table of interconversion studies.

FIG. 38: XRPD peak listing for crystalline solid form C (−)-halofenate.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “about” as used herein means variation one might see inmeasurements taken among different instruments, samples, and samplepreparations. Such variation may include, for instance, colligativeproperties for thermal measurements. Typical variation among differentx-ray diffractometers and sample preparations for crystalline solidforms is on the order of 0.2 °2θ. Typical variation for Raman and IRspectrometers is on the order of twice the resolution of thespectrometer. The resolution of the spectrometer used was about 2 cm⁻¹.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces in an amount of greater than about 0.3% whenprepared according to the invention.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces. Hydrates are formed by the combination of one or more moleculesof water with one of the substances in which the water retains itsmolecular state as H₂O, such combination being able to form one or morehydrate.

The term “anhydrous” as used herein means a compound of the invention ora salt thereof that contains less than about 3% by weight water orsolvent when prepared according to the invention.

The term “drying” as used herein means a method of removing solventand/or water from a compound of the invention which, unless otherwisespecified, may be done at atmospheric pressure or under reduced pressureand with or without heating until the level of solvent and/or watercontained reached an acceptable level.

The term “polymorphs” as used herein means crystal structures in which acompound can crystallize in different crystal packing arrangements, allof which have the same elemental composition. Different crystal formsusually have different X-ray diffraction patterns, infrared spectra,melting points/endotherm maximums, density hardness, crystal shape,optical and electrical properties, stability and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate.

The term “solid form” as used herein means crystal structures in whichcompounds can crystallize in different packing arrangements. Solid formsinclude polymorphs, hydrates, and solvates as those terms are used inthis invention. Different solid forms, including different polymorphs,of the same compound exhibit different x-ray powder diffraction patternsand different spectra including infra-red, Raman, and solid-state NMR.Their optical, electrical, stability, and solubility properties may alsodiffer.

The term “characterize” as used herein means to select data from ananalytical measurement such as X-ray powder diffraction, infra-redspectroscopy, Raman spectroscopy, and/or solid-state NMR to distinguishone solid form of a compound from other solid forms of a compound.

The term “mammal” includes, without limitation, humans, domestic animals(e.g., dogs or cats), farm animals (cows, horses, or pigs), monkeys,rabbits, mice, and laboratory animals.

The term “insulin resistance” can be defined generally as a disorder ofglucose metabolism. More specifically, insulin resistance can be definedas the diminished ability of insulin to exert its biological actionacross a broad range of concentrations producing less than the expectedbiologic effect (see, e.g., Reaven, G. M., J. Basic & Clin. Phys. &Pharm. (1998) 9: 387-406 and Flier, J. Ann Rev. Med. (1983) 34:145-60).Insulin resistant persons have a diminished ability to properlymetabolize glucose and respond poorly, if at all, to insulin therapy.Manifestations of insulin resistance include insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. Insulin resistance can causeor contribute to polycystic ovarian syndrome, Impaired Glucose Tolerance(IGT), gestational diabetes, hypertension, obesity, atherosclerosis anda variety of other disorders. Eventually, the insulin resistantindividuals can progress to a point where a diabetic state is reached.The association of insulin resistance with glucose intolerance, anincrease in plasma triglyceride and a decrease in high-densitylipoprotein cholesterol concentrations, high blood pressure,hyperuricemia, smaller denser low-density lipoprotein particles, andhigher circulating levels of plaminogen activator inhibitor-1), has beenreferred to as “Syndrome X” (see, e.g., Reaven, G. M., Physiol. Rev.(1995) 75: 473-486).

The term “diabetes mellitus” or “diabetes” means a disease or conditionthat is generally characterized by metabolic defects in production andutilization of glucose which result in the failure to maintainappropriate blood sugar levels in the body. The result of these defectsis elevated blood glucose, referred to as “hyperglycemia.” Two majorforms of diabetes are Type 1 diabetes and Type 2 diabetes. As describedabove, Type 1 diabetes is generally the result of an absolute deficiencyof insulin, the hormone which regulates glucose utilization. Type 2diabetes often occurs in the face of normal, or even elevated levels ofinsulin and can result from the inability of tissues to respondappropriately to insulin. Most Type 2 diabetic patients are insulinresistant and have a relative deficiency of insulin, in that insulinsecretion can not compensate for the resistance of peripheral tissues torespond to insulin. In addition, many Type 2 diabetics are obese. Othertypes of disorders of glucose homeostasis include Impaired GlucoseTolerance, which is a metabolic stage intermediate between normalglucose homeostasis and diabetes, and Gestational Diabetes Mellitus,which is glucose intolerance in pregnancy in women with no previoushistory of Type 1 or Type 2 diabetes.

The term “secondary diabetes” is diabetes resulting from otheridentifiable etiologies which include: genetic defects of β cellfunction (e.g., maturity onset-type diabetes of youth, referred to as“MODY,” which is an early-onset form of Type 2 diabetes with autosomalinheritance; see, e.g., Fajans S. et al., Diabet. Med. (1996) (9 Suppl6): S90-5 and Bell, G. et al., Annu. Rev. Physiol. (1996) 58: 171-86)genetic defects in insulin action; diseases of the exocrine pancreas(e.g., hemochromatosis, pancreatitis, and cystic fibrosis); certainendocrine diseases in which excess hormones interfere with insulinaction (e.g., growth hormone in acromegaly and cortisol in Cushing'ssyndrome); certain drugs that suppress insulin secretion (e.g.,phenytoin) or inhibit insulin action (e.g., estrogens andglucocorticoids); and diabetes caused by infection (e.g., rubella,Coxsackie, and CMV); as well as other genetic syndromes. The guidelinesfor diagnosis for Type 2 diabetes, impaired glucose tolerance, andgestational diabetes have been outlined by the American DiabetesAssociation (see, e.g., The Expert Committee on the Diagnosis andClassification of Diabetes Mellitus, Diabetes Care, (1999) Vol 2 (Suppl1): S5-19).

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes R and S are used to denotethe absolute configuration of the molecule about its chiral center(s).The prefixes “d” and “1” or (+) and (−) are employed to designate thesign of rotation of plane-polarized light by the compound, with (−) or 1meaning that the compound is “levorotatory” and with (+) or d is meaningthat the compound is “dextrorotatory”. There is no correlation betweennomenclature for the absolute stereochemistry and for the rotation of anenantiomer. For a given chemical structure, these compounds, called“stereoisomers,” are identical except that they are mirror images of oneanother. A specific stereoisomer can also be referred to as an“enantiomer,” and a mixture of such isomers is often called an“enantiomeric” or “racemic” mixture. See, e.g., Streitwiesser, A. &Heathcock, C. H., INTRODUCTION TO ORGANIC CHEMISTRY, 2^(nd) Edition,Chapter 7 (MacMillan Publishing Co., U.S.A. 1981). The optical rotation[α]_(D) of (−)-halofenate was measured in methyl alcohol.

“Chiral” or “chiral center” refers to a carbon atom having fourdifferent substituents. However, the ultimate criterion of chirality isnon-superimposability of mirror images.

The terms “CPTA” and “halofenic acid” refer to the acid form of4-Chlorophenyl-(3-trifluoromethylphenoxy)-acetic acid.

“Enantiomeric mixture” means a chiral compound having a mixture ofenantiomers, including a racemic mixture. Preferably, enantiomericmixture refers to a chiral compound having a substantially equal amountsof each enantiomers. More preferably, enantiomeric mixture refers to aracemic mixture where each enantiomer is present in an equal amount.

“Enantiomerically enriched” refers to a composition where one enantiomeris present in a higher amount than prior to being subjected to aseparation process.

“Enantiomeric excess” or “% ee” refers to the amount of differencebetween the first enantiomer and the second enantiomer. Enantiomericexcess is defined by the equation: % ee=(% of the first enantiomer)−(%of the second enantiomer). Thus, if a composition comprises 98% of thefirst enantiomer and 2% of the second enantiomer, the enantiomericexcess of the first enantiomer is 98%-2% or 96%.

“Optical purity” refers to the amount of a particular enantiomer presentin the composition. For example, if a composition comprises 98% of thefirst enantiomer and 2% of the second enantiomer, the optical purity ofthe first enantiomer is 98%.

“Derivative” refers to compounds such as those disclosed in U.S. Pat.No. 3,517,050.

The term “rate” when referring to a formation of a salt refers tokinetic and/or thermodynamic rates.

As used herein, the terms “treating”, “contacting” or “reacting” refersto adding or mixing two or more reagents under appropriate conditions toproduce the indicated and/or the desired product. It should beappreciated that the reaction which produces the indicated and/or thedesired product may not necessarily result directly from the combinationof two reagents which were initially added, i.e., there may be one ormore intermediates which are produced in the mixture which ultimatelyleads to the formation of the indicated and/or the desired product.

The term “substantially free of its (+) stereoisomer,” as used herein,means that the compositions contain a substantially greater proportionof the (−) isomer of halofenate in relation to the (+) isomer. In thepresent invention the term “(−)-halofenate” means that it issubstantially free of its (+) isomer. In one embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition is at least 90% by weight of the (−) isomer and 10% byweight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 91% by weight of the (−) isomer and 9%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 92% by weight of the (−) isomer and 8%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 93% by weight of the (−) isomer and 7%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 94% by weight of the (−) isomer and 6%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 95% by weight of the (−) isomer and 5%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 96% by weight of the (−) isomer and 4%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 97% by weight of the (−) isomer and 3%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” as used herein, means thatthe composition contains at least 98% by weight of the (−) isomer and 2%by weight or less of the (+) isomer. In another embodiment, the term“substantially free of its (+) stereoisomer,” means that the compositioncontains greater than 99% by weight of the (−) isomer. These percentagesare based upon the total amount of halofenate in the composition.

The term “substantially pure,” as used herein without reference to the(+) isomer, means that the compositions contain a substantially greaterproportion of the (−)-halofenate in relation to the sum of otherchemical compounds, other than solvent, including the (+)-isomer ofhalofenate, other crystalline solid forms of (−)-halofenate and theamorphous form, and chemical impurities, collectively “non-solventcompounds.” In one embodiment, the term “substantially pure,” as usedherein, means that the composition is at least 90% by weight of(−)-halofenate and 10% by weight or less of other non-solvent compounds.In one embodiment, the term “substantially pure,” as used herein, meansthat the composition is at least 91% by weight of (−)-halofenate and 9%by weight or less of other non-solvent compounds. In one embodiment, theterm “substantially pure,” as used herein, means that the composition isat least 92% by weight of (−)-halofenate and 8% by weight or less ofother non-solvent compounds. In one embodiment, the term “substantiallypure,” as used herein, means that the composition is at least 93% byweight of (−)-halofenate and 7% by weight or less of other non-solventcompounds. In one embodiment, the term “substantially pure,” as usedherein, means that the composition is at least 94% by weight of(−)-halofenate and 6% by weight or less of other non-solvent compounds.In one embodiment, the term “substantially pure,” as used herein, meansthat the composition is at least 95% by weight of (−)-halofenate and 5%by weight or less of other non-solvent compounds. In one embodiment, theterm “substantially pure,” as used herein, means that the composition isat least 96% by weight of (−)-halofenate and 4% by weight or less ofother non-solvent compounds. In one embodiment, the term “substantiallypure,” as used herein, means that the composition is at least 97% byweight of (−)-halofenate and 3% by weight or less of other non-solventcompounds. In one embodiment, the term “substantially pure,” as usedherein, means that the composition is at least 98% by weight of(−)-halofenate and 2% by weight or less of other non-solvent compounds.In one embodiment, the term “substantially pure,” as used herein, meansthat the composition is at least 99% by weight of (−)-halofenate and 1%by weight or less of other non-solvent compounds. In one embodiment, theterm “substantially pure,” as used herein, means that the composition isat least 99.5% by weight of (−)-halofenate and 0.5% by weight or less ofother non-solvent compounds. In another embodiment, the term“substantially pure,” as used herein, means that the compositioncontains at least 90% by weight of a particular crystalline solid oramorphous form of the (−)-isomer and 10% by weight or less of othercrystalline solid or amorphous forms of the (−)-isomer. In anotherembodiment, the term “substantially pure,” as used herein, means thatthe composition contains at least 90% by weight of a particularcrystalline solid or amorphous form of the (−)-isomer and 10% by weightor less of other crystalline solid or amorphous forms of the (−)-isomer.In another embodiment, the term “substantially pure,” as used herein,means that the composition contains at least 91% by weight of aparticular crystalline solid or amorphous form of the (−)-isomer and 9%by weight or less of other crystalline solid or amorphous forms of the(−)-isomer. In another embodiment, the term “substantially pure,” asused herein, means that the composition contains at least 92% by weightof a particular crystalline solid or amorphous form of the (−)-isomerand 8% by weight or less of other crystalline solid or amorphous formsof the (−)-isomer. In another embodiment, the term “substantially pure,”as used herein, means that the composition contains at least 93% byweight of a particular crystalline solid or amorphous form of the(−)-isomer and 7% by weight or less of other crystalline solid oramorphous forms of the (−)-isomer. In another embodiment, the term“substantially pure,” as used herein, means that the compositioncontains at least 94% by weight of a particular crystalline solid oramorphous form of the (−)-isomer and 6% by weight or less of othercrystalline solid or amorphous forms of the (−)-isomer. In anotherembodiment, the term “substantially pure,” as used herein, means thatthe composition contains at least 95% by weight of a particularcrystalline solid or amorphous form of the (−)-isomer and 5% by weightor less of other crystalline solid or amorphous forms of the (−)-isomer.In another embodiment, the term “substantially pure,” as used herein,means that the composition contains at least 96% by weight of aparticular crystalline solid or amorphous form of the (−)-isomer and 4%by weight or less of other crystalline solid or amorphous forms of the(−)-isomer. In another embodiment, the term “substantially pure,” asused herein, means that the composition contains at least 97% by weightof a particular crystalline solid or amorphous form of the (−)-isomerand 3% by weight or less of other crystalline solid or amorphous formsof the (−)-isomer. In another embodiment, the term “substantially pure,”as used herein, means that the composition contains at least 98% byweight of a particular crystalline solid or amorphous form of the(−)-isomer and 2% by weight or less of other crystalline solid oramorphous forms of the (−)-isomer. In another embodiment, the term“substantially pure,” as used herein, means that the compositioncontains at least 99% by weight of a particular crystalline solid oramorphous form of the (−)-isomer and 1% by weight or less of othercrystalline solid or amorphous forms of the (−)-isomer. In anotherembodiment, the term “substantially pure,” as used herein, means thatthe composition contains at least 99.5% by weight of a particularcrystalline solid or amorphous form of the (−)-isomer and 0.5% by weightor less of other crystalline solid or amorphous forms of the (−)-isomer.These percentages are based upon the total amount of halofenate in thecomposition.

The term “in an isolated form” means unmixed or unformulated withpharmaceutically acceptable excipients or carriers.

The term “hyperinsulinemia” refers to the presence of an abnormallyelevated level of insulin in the blood.

The term “secretagogue” means a substance or compound that stimulatessecretion. For example, an insulin secretagogue is a substance orcompound that stimulates secretion of insulin.

The term “hemoglobin” or “Hb” refers to a respiratory pigment present inerythrocytes, which is largely responsible for oxygen transport. Ahemoglobin molecule comprises four polypeptide subunits (two α chainsystems and two β chain systems, respectively). Each subunit is formedby association of one globin protein and one heme molecule which is aniron-protoporphyrin complex. The major class of hemoglobin found innormal adult hemolysate is adult hemoglobin (referred to as “HbA”; alsoreferred to HbA₀ for distinguishing it from glycated hemoglobin, whichis referred to as “HbA₁,” described infra) having α₂β₂ subunits. Tracecomponents such as HbA₂ (α₂δ₂) can also be found in normal adulthemolysate.

Among classes of adult hemoglobin HbAs, there is a glycated hemoglobin(referred to as “HbA₁,” or “glycosylated hemoglobin”), which may befurther fractionated into HbA_(1a1), HbA_(1a2), HbA_(1b), and HbA_(1c)with an ion exchange resin fractionation. All of these subclasses havethe same primary structure, which is stabilized by formation of analdimine (Schiff base) by the amino group of N-terminal valine in the βsubunit chain of normal hemoglobin HbA and glucose (or,glucose-6-phosphate or fructose) followed by formation of ketoamine byAmadori rearrangement.

The term “glycosylated hemoglobin” (also referred to as “HbA_(1c),”,“GHb”, “hemoglobin-glycosylated”, “diabetic control index” and“glycohemoglobin”; hereinafter referred to as “hemoglobin A_(1c)”)refers to a stable product of the nonenzymatic glycosylation of theβ-chain of hemoglobin by plasma glucose. Hemoglobin A_(1c) comprises themain portion of glycated hemoglobins in the blood. The ratio ofglycosylated hemoglobin is proportional to blood glucose level.Therefore, hemoglobin A_(1c) rate of formation directly increases withincreasing plasma glucose levels. Since glycosylation occurs at aconstant rate during the 120-day lifespan of an erythrocyte, measurementof glycosylated hemoglobin levels reflect the average blood glucoselevel for an individual during the preceding two to three months.Therefore determination of the amount of glycosylated hemoglobinHbA_(1c) can be a good index for carbohydrate metabolism control.Accordingly, blood glucose levels of the last two months can beestimated on the basis of the ratio of HbA_(1c) to total hemoglobin Hb.The analysis of the hemoglobin A_(1c) in blood is used as a measurementenabling long-term control of blood glucose level (see, e.g., Jain, S.,et al., Diabetes (1989) 38: 1539-1543; Peters A., et al., JAMA (1996)276: 1246-1252).

The term “symptom” of diabetes, includes, but is not limited to,polyuria, polydipsia, and polyphagia, as used herein, incorporatingtheir common usage. For example, “polyuria” means the passage of a largevolume of urine during a given period; “polydipsia” means chronic,excessive thirst; and “polyphagia” means excessive eating. Othersymptoms of diabetes include, e.g., increased susceptibility to certaininfections (especially fungal and staphylococcal infections), nausea,and ketoacidosis (enhanced production of ketone bodies in the blood).

The term “complication” of diabetes includes, but is not limited to,microvascular complications and macrovascular complications.Microvascular complications are those complications which generallyresult in small blood vessel damage. These complications include, e.g.,retinopathy (the impairment or loss of vision due to blood vessel damagein the eyes); neuropathy (nerve damage and foot problems due to bloodvessel damage to the nervous system); and nephropathy (kidney diseasedue to blood vessel damage in the kidneys). Macrovascular complicationsare those complications which generally result from large blood vesseldamage. These complications include, e.g., cardiovascular disease andperipheral vascular disease. Cardiovascular disease refers to diseasesof blood vessels of the heart. See. e.g., Kaplan, R. M., et al.,“Cardiovascular diseases” in HEALTH AND HUMAN BEHAVIOR, pp. 206-242(McGraw-Hill, New York 1993). Cardiovascular disease is generally one ofseveral forms, including, e.g., hypertension (also referred to as highblood pressure), coronary heart disease, stroke, and rheumatic heartdisease. Peripheral vascular disease refers to diseases of any of theblood vessels outside of the heart. It is often a narrowing of the bloodvessels that carry blood to leg and arm muscles.

The term “atherosclerosis” encompasses vascular diseases and conditionsthat are recognized and understood by physicians practicing in therelevant fields of medicine. Atherosclerotic cardiovascular disease,coronary heart disease (also known as coronary artery disease orischemic heart disease), cerebrovascular disease and peripheral vesseldisease are all clinical manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

The term “antihyperlipidemic” refers to the lowering of excessive lipidconcentrations in blood to desired levels.

The term “hyperlipidemia” refers to the presence of an abnormallyelevated level of lipids in the blood. Hyperlipidemia can appear in atleast three forms: (1) hypercholesterolemia, i.e., an elevatedcholesterol level; (2) hypertriglyceridemia, i.e., an elevatedtriglyceride level; and (3) combined hyperlipidemia, i.e., a combinationof hypercholesterolemia and hypertriglyceridemia.

The term “modulate” refers to the treating, prevention, suppression,enhancement or induction of a function or condition. For example, thecompounds of the present invention can modulate hyperlipidemia bylowering cholesterol in a human, thereby suppressing hyperlipidemia.

The term “treating” also means the management and care of a humansubject for the purpose of combating the disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, alleviating thesymptoms or complications, or eliminating the disease, condition, ordisorder.

The term “cholesterol” refers to a steroid alcohol that is an essentialcomponent of cell membranes and myelin sheaths and, as used herein,incorporates its common usage. Cholesterol also serves as a precursorfor steroid hormones and bile acids.

The term “triglyceride(s)” (“TGs”), as used herein, incorporates itscommon usage. TGs consist of three fatty acid molecules esterified to aglycerol molecule and serve to store fatty acids which are used bymuscle cells for energy production or are taken up and stored in adiposetissue.

Because cholesterol and TGs are water insoluble, they must be packagedin special molecular complexes known as “lipoproteins” in order to betransported in the plasma. Lipoproteins can accumulate in the plasma dueto overproduction and/or deficient removal. There are at least fivedistinct lipoproteins differing in size, composition, density, andfunction. In the cells of the small of the intestine, dietary lipids arepackaged into large lipoprotein complexes called “chylomicrons”, whichhave a high TG and low-cholesterol content. In the liver, TG andcholesterol esters are packaged and released into plasma as TG-richlipoprotein called very low density lipoprotein (“VLDL”), whose primaryfunction is the endogenous transport of TGs made in the liver orreleased by adipose tissue. Through enzymatic action, VLDL can be eitherreduced and taken up by the liver, or transformed into intermediatedensity lipoprotein (“IDL”). IDL, is in turn, either taken up by theliver, or is further modified to form the low density lipoprotein(“LDL”). LDL is either taken up and broken down by the liver, or istaken up by extrahepatic tissue. High density lipoprotein (“HDL”) helpsremove cholesterol from peripheral tissues in a process called reversecholesterol transport.

The term “dyslipidemia” refers to abnormal levels of lipoproteins inblood plasma including both depressed and/or elevated levels oflipoproteins (e.g., elevated levels of LDL, VLDL and depressed levels ofHDL).

Exemplary Primary Hyperlipidemia include, but are not limited to, thefollowing:

(1) Familial Hyperchylomicronemia, a rare genetic disorder which causesa deficiency in an enzyme, LP lipase, that breaks down fat molecules.The LP lipase deficiency can cause the accumulation of large quantitiesof fat or lipoproteins in the blood;

(2) Familial Hypercholesterolemia, a relatively common genetic disordercaused where the underlying defect is a series of mutations in the LDLreceptor gene that result in malfunctioning LDL receptors and/or absenceof the LDL receptors. This brings about ineffective clearance of LDL bythe LDL receptors resulting in elevated LDL and total cholesterol levelsin the plasma;

(3) Familial Combined Hyperlipidemia, also known as multiplelipoprotein-type hyperlipidemia; an inherited disorder where patientsand their affected first-degree relatives can at various times manifesthigh cholesterol and high triglycerides. Levels of HDL cholesterol areoften moderately decreased;

(4) Familial Defective Apolipoprotein B-100 is a relatively commonautosomal dominant genetic abnormality. The defect is caused by a singlenucleotide mutation that produces a substitution of glutamine forarginine which can cause reduced affinity of LDL particles for the LDLreceptor. Consequently, this can cause high plasma LDL and totalcholesterol levels;

(5) Familial Dysbetaliproteinemia, also referred to as Type IIIHyperlipoproteinemia, is an uncommon inherited disorder resulting inmoderate to severe elevations of serum TG and cholesterol levels withabnormal apolipoprotein E function. HDL levels are usually normal; and

(6) Familial Hypertriglyceridemia, is a common inherited disorder inwhich the concentration of plasma VLDL is elevated. This can cause mildto moderately elevated triglyceride levels (and usually not cholesterollevels) and can often be associated with low plasma HDL levels.

Risk factors in exemplary Secondary Hyperlipidemia include, but are notlimited to, the following: (1) disease risk factors, such as a historyof Type 1 diabetes, Type 2 diabetes, Cushing's syndrome, hypothyroidismand certain types of renal failure; (2) drug risk factors, whichinclude, birth control pills; hormones, such as estrogen, andcorticosteroids; certain diuretics; and various β blockers; (3) dietaryrisk factors include dietary fat intake per total calories greater than40%; saturated fat intake per total calories greater than 10%;cholesterol intake greater than 300 mg per day; habitual and excessivealcohol use; and obesity.

The terms “obese” and “obesity” refers to, according to the World HealthOrganization, a Body Mass Index (BMI) greater than 27.8 kg/m² for menand 27.3 kg/m² for women (BMI equals weight (kg)/height (m²). Obesity islinked to a variety of medical conditions including diabetes andhyperlipidemia. Obesity is also a known risk factor for the developmentof Type 2 diabetes (See, e.g., Barrett-Conner, E., Epidemol. Rev. (1989)11: 172-181; and Knowler, et al., Am. J Clin. Nutr. (1991)53:1543-1551).

II. Solid and Amorphic Embodiments of the Invention and theirPreparation

The present invention is directed to (−)-halofenate in a substantiallypure crystalline solid and/or amorphous form and processes for theirpreparation and pharmaceutical compositions comprising these forms andthese forms in an isolated form. (−)-Halofenate has the followinggeneral formula:

The chemical synthesis of the racemic mixture of halofenate can beperformed by the methods described in U.S. Pat. No. 3,517,050, theteaching of which is incorporated herein by reference. The individualenantiomers can be obtained by resolution of the racemic mixture ofenantiomers by the methods described in U.S. Pat. No. 6,262,118 and U.S.Patent Application Ser. No. 60/608,927, and using conventional meansknown to and used by those of skill in the art (see, e.g., Jaques, J.,et al., in ENANTIOMERS, RACEMATES, AND RESOLUTIONS, John Wiley and Sons,New York (1981), the teachings of which are incorporated herein byreference). Other standard methods of resolution known to those skilledin the art, including but not limited to, simple crystallization andchromatographic resolution, can also be used (see, e.g., STEREOCHEMISTRYOF CARBON COMPOUNDS (1962) E. L. Eliel, McGraw Hill; Lochmuller, J.Chromatography (1975) 113, 283-302). Additionally, optically pureisomers can be prepared from the racemic mixture by enzymaticbiocatalytic resolution. Enzymatic biocatalytic resolution has beendescribed previously (see, e.g., U.S. Pat. Nos. 5,057,427 and 5,077,217,the disclosures of which are incorporated herein by reference). Othermethods of obtaining enantiomers include stereospecific synthesis (see,e.g., Li, A. J. et al., Pharm. Sci. (1997) 86:1073-1077).

In developing a process for production of (−)-halofenate as an activepharmaceutical ingredient (API), two factors were of great importance:the impurity profile and the crystal morphology of (−)-halofenate. Theresults from initial isolation and crystallization work showed that theimpurity profile of (−)-halofenate mainly consisted of CPTA whoseabundances ranged from 1.07 to 3.9%. Preferably the API has levels ofimpurities below 0.2% and is in the most thermodynamically stablecrystalline solid form. The difficulty in controlling the level ofimpurities and the crystalline solid nature of the API required thedevelopment of a process for the production of (−)-halofenate to providethe requisite purity and the proper crystal form. Subsequent isolationand crystallization work indicated that there were at least fivecrystalline solid forms (designated as Forms A, B, C, D and E) and anamorphous form of the API. In one embodiment, the present inventionprovides (−)-halofenate in new crystalline forms designated as Form A,Form B, Form C, Form D, Form E as well as an amorphous form.

The solid forms of the invention may be described by one or more ofseveral techniques including X-ray powder diffraction, Ramanspectroscopy, IR spectroscopy, and thermal methods. Further,combinations of such techniques may be used to describe the invention.For example, one or more X-ray powder diffraction peaks combined withone or more Raman peaks may be used to describe one or more solid formsof the invention in a way that differentiates it from the other solidforms.

Although it characterizes a form, it is not necessary to rely only uponan entire diffraction pattern or spectrum to characterize a solid form.Those of ordinary skill in the pharmaceutical arts recognize that asubset of a diffraction pattern or spectrum may be used to characterizea solid form provided that subset distinguishes the solid form from theother forms being characterized. Thus, one or more X-ray powderdiffraction peaks alone may be used to characterize a solid form.Likewise, one or more IR peaks alone or Raman peaks alone may be used tocharacterize a solid form. Such characterizations are done by comparingthe X-ray, Raman, and IR data amongst the forms to determinecharacteristic peaks.

One may also combine data from other techniques in such acharacterization. Thus, one may rely upon one or more peaks from anx-ray powder diffraction and for example, Raman or IR data, tocharacterize a form. For example, if one or more x-ray peakscharacterize a form, one could also consider Raman or IR data tocharacterize the form. It is sometimes helpful to consider Raman data,for example, in pharmaceutical formulations.

Initial examination of the D morphology of (−)-halofenate identified thefirst three distinct crystal forms: forms A, B and C. The polymorphswere identified at three stages of the crystallization process from 6/1(v/v) heptane/2-propanol. (1) Crystalline form B was isolated aftercrystallization of the crude wet-cake from 25% aqueous isopropylalcohol, (2) crystalline form C was formed after drying the crudewet-cake to effect solvent removal, and (3) crystalline solid form A wasformed after complete solvent removal. Using the protocols described inthe Examples, these three polymorphs could be generated andinterconverted, demonstrating the concurrency between solventincorporation and polymorph interconversion.

Thus filtration of a slurry of (−)-halofenate in 6/1 heptane/2-propanol(IPA) followed by drying the isolated white crystalline solid at roomtemperature under reduced pressure gave the morphologically distinctcrystalline solid (−)-halofenate/form B. FIGS. 15 and 13 respectivelyshow the DSC trace and the X-ray powder pattern for the crystallinesolid. In the DSC trace, the sharpness of the endotherm peak at about71° C. is particularly noteworthy, and in the X-ray powder diffractionpattern, the peaks at about 6.2 °2θ and about 12.4 °2θ arecharacteristic peaks of the pattern (for a discussion of the theory ofX-ray powder diffraction patterns see “X-ray diffraction procedures” byH. P. Klug and L. E. Alexander, J. Wiley, New York (1974)). The peaks atabout 6.2 °2θ and about 12.4 °2θ characterize Form B with respect toForms A, C, D, and E because none of those forms have peaks to within0.4 2θ, twice approximate precision of X-ray powder diffraction peaks,of the two Form B peaks.

Because the typical variation in any given x-ray powder diffraction peakis on the order of 0.2° 2θ, when selecting peaks to characterize apolymorph, one selects peaks that are at least twice that value (i.e.,0.4°θ) from a peak from another polymorph. Thus, in a particularpolymorph x-ray pattern, a peak that is at least 0.4°θ from a peak inanother polymorph is eligible to be considered as a peak that can eitheralone or together with another peak be used to characterize thatpolymorph. In the case of Form B, the set of peaks at about 6.2° 2θ andabout 12.4° 2θ are at least 0.4° θ away from peaks in any of Forms A, C,D, or E as illustrated in table 1. Tables 1 and 2 identify the mainpeaks of Forms A, B, C, D and E.

The data in those tables come from FIGS. 2, 14, 19, 27 and 32 whichreport two-theta angles to four decimal places. Because the variabilityof x-ray data is in the first decimal place, the invention is describedto one decimal point. For example, the peak listed in table 2 as 22.05originates in FIG. 2 as 22.0479 °2θ. To one decimal point, this value is22.0 °2θ, not 22.1 °2θ. Thus, the value of “about 22.0 °2θ” is used tohelp describe the invention where appropriate not “about 22.1 °2θ.”Likewise, the value of 17.45 °2θ in table 2 originates from FIG. 19 as17.4451 °2θ and, therefore, is rounded to 17.4 °2θ and not 17.5°2θ. Fromthat list, one sees that the peak at about 6.2 °2θ (on the table listedas 6.16 °2θ), when taken to one decimal point, is greater than 0.4 °2θaway from any peak in Forms A, C or D. Thus, the peak at about 6.2 °2θcan be used to distinguish Form B from Form A, C and D. It cannot, byitself, be used to distinguish over Form E because that form contains apeak at about 6.4 °2θ (6.43 °2θ in Tables 1 and 2). Thus, more data isrequired to differentiate Form B from Form E. The peak at about 12.4 °2θ(12.42 °2θ in Tables 1 and 2) is more than 0.4 °2θ away from any peak inForm E.

Although the peak list for Form E in FIG. 27 lists a peak at about 12.4°2θ, intensity at that position in the actual pattern in FIG. 26 is notdiscernable from noise and indeed the intensity of the listed peak inFIG. 27 is only 4% of the maximum peak. For this reason, what FIG. 27calls a peak at about 12.4° 2θ is not a peak and was not included in thepeak list of table 1. By comparison, the X-ray powder diffractionpattern of Form B in FIG. 13 has a clearly discernable peak at about12.4° 2θ. Thus, the peak at about 12.4° 2θ can be used to distinguishForm B from Form E. Thus, the Form B peaks at about 6.2 °2θ and 12.4 °2θcharacterize Form B with respect to Forms A, C, D, and E. The solid formisolated at this stage in the process contained between about 2% andabout 3% solvent by weight and could be converted to other solid formsupon drying or slurrying.

TABLE 1 (−)-Halofenate XRPD Peak (°2θ) and Relative Intensity Listing(I/I₁) Amorphous Form A Form B Form C Form D Form E Broad peak °2 θ I/I₁°2 θ I/I₁ °2 θ I/I₁ °2 θ I/I₁ °2 θ I/I₁ between (°2 θ): 7.26 13 6.16 819.86 19 4.59 34 5.87 17 15 and 30 7.75 9 6.96 9 13.30 88 9.62 31 6.43 148.96 6 10.24 5 14.04 4 15.86 8  8.94 (broad) 12 10.79 18 11.75 6 14.6733 16.28 18 10.85 (broad) 6 13.08 36 12.42 21 15.53 43 17.45 100 11.7970 13.50 17 14.01 12 15.94 7 18.34 12 12.97 17 14.72 53 15.74 4 16.42 518.74 14 13.64 17 15.40 19 17.45 8 20.38 86 19.30 23 14.70 10 17.91 4918.22 12 21.34 25 20.00 7 15.41 (broad) 8 18.96 41 18.78 100 21.86 620.40 27 17.73 43 20.09 29 19.47 13 23.12 58 21.36 76 18.12 12 21.08 3820.06 51 24.88 16 24.26 29 18.59 100 21.64 26 20.50 33 25.85 100 24.5251 18.97 29 22.05 100 21.26 15 26.81 38 25.17 34 19.72 65 22.40 19 22.5421 27.34 21 26.26 (broad) 6 20.08 24 23.47 57 23.52 12 28.69 9 21.28 8524.41 18 23.82 23 30.18 21 22.38 50 25.59 33 25.28 13 30.71 18 23.62 5926.92 (broad) 20 25.95 14 31.23 13 24.39 (broad) 17 27.91 (broad) 926.80 9 31.94 33 26.80 44 29.33 (broad) 16 27.24 10 32.77 18 30.66(broad) 13 27.71 10 36.14 6 31.26 (broad) 9 28.24 7 37.35 (broad) 329.66 (broad) 6 38.17 16 31.67 7

TABLE 2 Unique Crystalline (−)-Halofenate XRPD Peaks (no other peakswithin ± 0.4 °2θ make up a unique set for each crystalline form) to twosignificant figures after the decimal point Form A Form B Form C Form DForm E °2θ °2θ °2θ °2θ °2θ 10.79 6.16 9.86 9.62 11.79 22.05 12.42 13.3017.45 12.97 29.33

Preferred orientation can affect peak intensities, but not peakpositions, in XRPD patterns. In the case of (−)-halofenate, preferredorientation has the most effect on the region of 22-30 °2θ. Preferredorientation causes some peaks in this region to be diminished (orincreased) and less resolved from each other. Crystal habit does notclearly differentiate between the solid forms; a variety of habits havebeen observed for each of the forms, including needles, blades, plates,and irregular-shaped particles.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an X-ray powder diffraction pattern substantially in accordance withFIG. 13; and

(ii) a DSC scan substantially in accordance with FIG. 15;

herein designated as Form B.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an X-ray powder diffraction pattern comprising peaks at about 6.2°2θ and about 12.4 °2θ; and

(ii) a DSC endotherm maximum of about 71° C.;

herein designated as Form B.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides an X-ray powder diffraction pattern comprising peaks at about6.2 °2θ and about 12.4 °2θ herein designated as Form B.

In yet another embodiment of the invention, the invention relates to(−)halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 6.2 °2θ, about 12.4 °2θ, and at least one peak selectedfrom about 18.8 °2θ, about 20.1 °2θ, and about 14.0 °2θ; hereindesignated as Form B.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a DSC endotherm maximum of about 71° C.;

herein designated as Form B.

When the resultant wetcake was further dried under reduced pressure at50° C., a white crystalline solid, polymorph C was isolated. FIGS. 17and 16 respectively show the DSC trace and the X-ray powder pattern forthis crystalline solid. These results were observed when the level ofheptane was lowered to at about 0.3 wt %. This data shows that 0.3 wt %or more of heptane was necessary to cause polymorph interconversion fromform C to form A. In the DSC trace, a weak transition at about 75° C. isnoteworthy, however the peaks at about 9.9 °2θ and about 13.3 °2θ in theX-ray powder diffraction pattern characterize Form C with respect toForms A, B, D, and E. Because none of those forms have peaks to within0.4 2θ, the approximate precision of X-ray powder diffraction peaks, ofthe two characteristic Form C peaks (see Tables 1 and 2). From thatlist, one sees that the peaks at about 9.9 °2θ and 13.3 °2θ (in Tables 1and 2 listed as 9.86 °2θ and 13.30 °2θ, respectively), when taken to onedecimal point, is greater than 0.4 °2θ away from any peak in Forms A, B,D or E. Thus, the peaks at about 9.9 °2θ and 13.3 °2θ can be used todistinguish Form B from Forms A, B, D and E. Form C could be convertedto other forms upon drying or slurrying.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, wherein thecompound provides at least one of:

(i) an X-ray powder diffraction pattern substantially in accordance withFIG. 17; and

(ii) a DSC scan substantially in accordance with FIG. 16; hereindesignated as Form C.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides wherein the compound provides an X-ray powder diffractionpattern comprising peaks at about 9.9 °2θ and about 13, 3 °2θ; hereindesignated as Form C.

In yet another embodiment of the invention, the invention relates to(−)halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 9.9° 2θ, about 13.3° 2θ, and at least one peak selectedfrom about 15.5 °2θ, about 23.1 °2θ, about 14.7 °2θ, and about 25.9 °2θ;herein designated as Form C.

The conversion of form C to form A was effected by further drying thewhite, crystalline solid at 50° C. under reduced pressure. FIGS. 3, 7and 1 respectively show the IR spectrum, the DSC trace, and the X-raypowder pattern for this crystalline solid. These results were observedwhen the remaining solvent was removed. A comparison of these data withthe data presented for other crystalline solid forms of (−)-halofenateclearly indicates that this crystalline solid has a unique crystallinesolid form. Differential scanning calorimetry (DSC) of form A of(−)-halofenate defined an endothermic onset of melting at 78° C. with anendotherm maximum of approximately 80° C. (see FIG. 10). Hot stagemicroscopy showed an onset of melting at approximately 73° C. withcompletion of melt at approximately 76° C. (See FIG. 8). The strongtransition at 80° C. in the DSC trace contrasts with the peaks at 71 and75° C. shown in FIGS. 15 and 17. Decomposition occurred with an onset atapproximately 200° C. The melted solid did not recrystallize uponcooling as evidenced by the lack of an exothermic event during cyclicDSC experiments, but the material appears to crystallize from a melt ina closed system as examined by light microscopy (see FIG. 9). The X-raypowder diffraction pattern definitively proves that this crystallinesolid is unique when compared to polymorph B. The pattern ischaracterized by peaks at about 10.8, °2θ about 22.0 °2θ, and about 29.3°2θ which are clearly different from those obtained for form B (seeTables 1 and 2). The peaks at about 10.8 °2θ, about 22.0 °2θ, and atabout 29.3 °2θ characterize Form A because none of Forms B, D, or Econtain three peaks that are within 0.4 °2θ of about 10.8 °2θ, about22.0 °2θ, and about 29.3 °2θ, respectively. Form A exhibits an endothermmaximum at about 80° C. by DSC and Form C melts at about 75° C. by DSC.Thus, one can use DSC, when the measurement is done according to theoperating parameters of the invention, to distinguish Form A from FormC. Accordingly, the Form A X-ray diffraction peaks at about 10.8 °2θ,about 22.0 °2θ, and about 29.3 °2θ together with a DSC maximum endothermat about 80° C. characterize Form A with respect to Forms B, C, D, andE. It is an anhydrous material as indicated by the 0.16% weight lossfrom 25 to 100° C. in the TGA. The material was also shown to benon-hygroscopic with no weight gain at 65% relative humidity (RH) andonly 1.6% weight gain at 65-95% RH, which was essentially unchangedafter moisture sorption analysis. All of the weight gain was lost in adesorption study at 5% RH (see FIG. 11). The solution phase ¹H NMRspectra showed Form A contained less than 0.05% solvents (see FIG. 12).The crystalline solid isolated at this stage in the process provided themost thermodynamically stable crystalline white solid and could bestored for long periods (months) without decomposition.

Generation of the crystal form A also occurred by crystallization fromacetonitrile, benzene, cyclohexanol, t-butyl methyl ether, methanol,methyl ethyl ketone, toluene, tetrahydrofuran and combinations thereof.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an infra red spectrum substantially in accordance with FIG. 3;

(ii) a Raman spectrum substantially in accordance with FIG. 5;

(iii) an X-ray powder diffraction pattern substantially in accordancewith FIG. 1; and

(iv) a DSC scan substantially in accordance with FIG. 7;

herein designated as Form A.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides an IR spectrum substantially in accordance with FIG. 3; hereindesignated as Form A.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a Raman spectrum substantially in accordance with FIG. 5;herein designated as Form A.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an infra red spectrum comprising absorption peaks at about 3479,3322, 3082, 2886, 2842, 1918, 1850, 1753, 1709, 1651, 1596, 1548, 1494,1461, 1430, 1371, 1340, 1272, 1231, 1127, 1070, 1017, 926, 903 and 884expressed in wave number cm⁻¹;

(ii) a Raman spectrum comprising absorption peaks at about 3087, 3071,2959, 2933, 2857, 1747, 1663, 1647, 1622, 1598, 1451, 1433, 1333, 1290,1274, 1231, 1208, 1177, 1095, 1015, 1001, 964, 948, 926, 905, 882, 872,833, 767, 757, 723 and 631 expressed in wave number cm⁻¹;(iii) an X-ray powder diffraction pattern comprising peaks at about 10.8°2θ about 22.0 °2θ, and about 29.3 °2θ and(iv) a DSC endotherm maximum of about 80° C.herein designated as Form A.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides an X-ray powder diffraction pattern comprising peaks at about10.8 °2θ, about 22.0 °2θ and about 29.3 °2θ herein designated as Form A.

In yet another embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 10.8° 2θ, about 22.0° 2θ, about 29.3° 2θ, and an infraredspectrum comprising at lease one peak selected from about 3322 cm-1 andabout 2886 cm-1; herein designated as Form A.

In a further embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 10.8 °2θ, about 22.0 °2θ, about 29.3 °2θ, and a Ramanspectrum comprising at least one peak selected from about 3087 cm⁻¹ andabout 1663 cm⁻¹; herein designated as Form A.

In an additional embodiment of the invention, the invention relates to(−)halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 10.8° 2θ, about 22.0° 2θ, about 29.3° 2θ, an infraredspectrum comprising at lease one peak selected from about 3322 cm-1 andabout 2886 cm-1, and a Raman spectrum comprising at least one peakselected from about 3087 cm-1 and about 1663 cm-1 herein designated asForm A.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a DSC endotherm maximum of about 80° C.; herein designated asForm A.

The interconversion of forms B and C to A can also be effected bycrystallizing the respective melts. Thus B may be converted to A eitherdirectly or B may be converted to A via C by these newly discoveredprocesses. Both processes produce the single, thermodynamically moststable polymorph A of (−)-halofenate in greater than 99% chemicalpurity. Later analysis of a sample of crystal form C also showed thatover time conversion to crystal form E (below) occurred.

The dependence of the process on the solvent system was studied and twoadditional solid forms D and E were identified. Solubility studies weredone on Form A in water and a variety of organic solvents. The data issummarized in FIG. 36. In general, (−)-halofenate was fairly soluble in(greater than 300 mg/mL) in most organic solvents tested, the exceptionsbeing water and very non-polar solvents (i.e. cyclohexane, hexanes,heptanes and 2,2,4-trimethylpentane). For these solvents, ambientsolubility was less than 1 mg/mL. Solubility was also determined inthese solvents at approximately 50° C. (see FIG. 36). In general,elevating the temperature increased the solubility of (−)-halofenateexcept in water for which there was no measurable increase. While Form Ais preferred for formulations, it exhibits lower solubility andtherefore requires higher temperatures and longer times to dissolve insome crystallization solvents.

Generation of the crystal form D occurred by crystallization fromacetone or ethanol. FIGS. 20, 24 and 18 respectively show the IRspectrum, the DSC trace and the X-ray powder pattern for thiscrystalline solid. All of the characterization data was obtained using asample prepared from dichloromethane. A comparison of these data withthe data presented above clearly indicates that this crystalline solidhas a unique solid form. A comparison of the XRPD pattern of Form D toother forms of (−)-halofenate is shown in Table 2. The X-ray powderdiffraction pattern definitively proves that this crystalline solid isunique when compared to polymorphs A, B, C and E. The pattern ischaracterized by peaks at about 9.6 °2θ and about 17.4 °2θ clearlydifferent from those obtained for forms A, B C and E. The peaks at about9.6 °2θ and at about 17.4 °2θ characterize Form D with respect to FormsA, B, C and E because none of these other forms contain two peaks thatare within 0.4 °2θ of 9.6 °2θ and 17.4 °2θ respectively. The DSC of formD of (−)-halofenate defined an endothermic onset of melting at about 72°C. with a endotherm maximum of approximately about 74° C. (see FIG. 24).Hot stage microscopy showed an onset of melting at approximately 73° C.with a complete melt at approximately 74° C. Decomposition occurred withon onset at approximately 225° C. The transition at 74° C. in the DSCtrace contrasts with those at 80° C., 71° C., 75° C. and 75° C. shownfor Forms A-C and E. Form D exhibited an approximate 0.15% weight lossfrom approximately 25-100° C. (FIG. 25). The TGA weight loss is probablydue to trace amounts of surface water as seen in ¹H NMR spectrum (FIG.12). No other solvent was detected by NMR, which confirms that Form D isanhydrous. The non-hygroscopicity of Form D was established by amoisture sorption/desorption study. A sample of Form D showed negligibleweight gain (less than 0.1% at 95% RH (see FIG. 25). The crystallinesolid resulting from the moisture sorption/desorption remained Form D.Other spectroscopic data acquired for Form D: FT-IR (see FIGS. 21-22)and FT-Raman (see FIGS. 23-24) showed that form D is distinguishablefrom other forms by these methods (see Tables 3 and 4). Form D could beconverted to Form A upon slurring.

TABLE 3 IR Peak Listing for (−)-Halofenate (peaks > 400 cm⁻¹) PeakPositions in Wavenumbers (cm⁻¹) Form A Form D Form E 3479 3469 3475 33223297 3301 3082 3086 3092 2886 2968 2969 2842 2930 2933 1918 2870 28711850 1747 1750 1753 1740 1706 1709 1703 1660 1651 1647 1597 1596 15971563 1548 1554 1493 1494 1492 1460 1461 1460 1429 1430 1429 1370 13711369 1338 1340 1345 1232 1272 1295 1178 1231 1232 1126 1127 1209 10701070 1193 1015 1017 1124 906 926 1069 886 903 1015 820 884 906 880 838819

TABLE 4 Raman Peak Listing for (−)-Halofenate (peaks > 400 cm⁻¹) PeakPositions in Wavenumbers (cm⁻¹) Form A Form D Form E 3087 3077 3071 30713063 2969 2959 2970 2933 2933 2932 1746 2857 1743 1657 1747 1649 16211663 1621 1598 1647 1598 1448 1622 1430 1432 1598 1329 1334 1451 12081291 1433 1192 1232 1333 1182 1179 1290 1093 1094 1274 1000 1001 1231936 907 1208 906 881 1177 881 767 1095 756 756 1015 723 722 1001 632 632964 948 926 905 882 872 833 767 757 723 631

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an infra red spectrum substantially in accordance with FIG. 20;

(ii) a Raman spectrum substantially in accordance with FIG. 22; and

(iii) an X-ray powder diffraction pattern substantially in accordancewith FIG. 18; and

(iv) a DSC scan substantially in accordance with FIG. 24;

herein designated as Form D.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides an infra red spectrum substantially in accordance with FIG. 20;

herein designated as Form D.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a Raman spectrum substantially in accordance with FIG. 22;

herein designated as Form D.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an infra red spectrum comprising absorption peaks at about 3469,3297, 3086, 2968, 2930, 2870, 1747, 1740, 1703, 1647, 1597, 1554, 1492,1460, 1429, 1369, 1345, 1295, 1232, 1209, 1193, 1124, 1069, 1015, 906,880, 838 and 819 cm⁻¹;

(ii) a Raman spectrum comprising absorption peaks at about 3077, 3063,2970, 2932, 1743, 1649, 1621, 1598, 1430, 1329, 1208, 1192, 1182, 1093,1000, 936, 906, 881, 756, 723 and 632 cm⁻¹;

(iii) an X-ray powder diffraction pattern comprising peaks at about 9.6°2θ and about 17.4 °2θ; and

(iv) a DSC endotherm maximum at about 74° C.;

herein designated as Form D.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides an X-ray powder diffraction pattern comprising peaks at about9.6 °2θ and about 17.4 °2θ; herein designated as Form D.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a DSC endotherm maximum at about 74° C.;

herein designated as Form D.

In yet another embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 9.6 °2θ, about 17.4 °2θ, and an infrared spectrumcomprising peaks at least one peak selected from about 3469 cm⁻¹ andabout 2870 cm⁻¹; herein designated as Form D.

In a further embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 9.6 °2θ, about 17.4 °2θ, and a Raman spectrum comprisingat least one peak selected from about 3077 cm⁻¹ and about 1329 cm⁻¹;herein designated as Form D.

In an additional embodiment of the invention, the invention relates to(−)halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 9.6° 2θ, about 17.4° 2θ, an infrared spectrum comprisingpeaks at least one peak selected from about 3469 cm⁻¹ and about 2870cm⁻¹, and a Raman spectrum comprising at least one peak selected fromabout 3077 cm⁻¹ and about 1329 cm⁻¹; herein designated as Form D.

Generation of the crystal form E occurred by crystallization fromheptane and t-butyl methyl ether. FIGS. 28, 32 and 26 respectively showthe IR spectrum, the DSC trace, and the X-ray powder pattern for thiscrystalline solid. A comparison of the XRPD pattern of Form E to otherforms of (−)-halofenate is shown in Tables 1 and 2 and clearly indicatesthat this crystalline solid has a unique solid form. The pattern ischaracterized by peaks at about 11.8 °2θ, and about 13.0 °2θ which aredifferent from those obtained for forms A-D. The peaks at about 11.8°2θ, and about 13.0 °2θ characterize Form E because none of Forms A, B,C or D contain a peak that is within 0.4 °2θ of about 11.8 °2θ and about13.0 °2θ. The DSC shows major endotherms at 75 and 80° C. The firstendothermic transition at 75° C. was shown to be the onset of a meltingtransition by hot stage microscopy (FIG. 33) and therefore after thefirst melt, form interconversion may occur. The second endothermpossibly corresponds to the melting of Form A at 80° C. Decompositionoccurred with on onset at approximately 225° C. Form E exhibited anapproximate 0.42% with loss from approximately 25-100° C. (FIG. 34) TheTGA weight loss is probably due to trace amounts of surface water asseen in ¹H NMR spectrum (see FIG. 12). No other solvent was detected byNMR, which confirms that Form E is anhydrous. The non-hygroscopicity ofForm E was established by a moisture sorption/desorption study. A sampleof Form E showed negligible weight gain (less than 0.2% at 95% RH, seeFIG. 34). The crystalline solid resulting from the moisturesorption/desorption remained Form E. Other spectroscopic data acquiredfor Form E (FT-IR, FIGS. 28-29 and FT-Raman, FIGS. 30-31) showed thatForm E can be distinguished by these methods. Form E could be convertedto Form A upon slurring.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) a infra red spectrum substantially in accordance with FIG. 28;

(ii) a Raman spectrum substantially in accordance with FIG. 30; and

(iii) a X-ray powder diffraction pattern substantially in accordancewith FIG. 26;

herein designated as Form E.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a infra red spectrum substantially in accordance with FIG. 28;

herein designated as Form E.

Thus in one embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides a Raman spectrum substantially in accordance with FIG. 30;

herein designated as Form E.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides at least one of:

(i) an infra red spectrum comprising absorption peaks at about 3475,3301, 3092, 2969, 2933, 2871, 1750, 1706, 1660, 1597, 1563, 1493, 1460,1429, 1370, 1338, 1232, 1178, 1126, 1070, 1015, 906, 886 and 820 cm⁻¹;

(ii) a Raman spectrum comprising absorption peaks at about 3071, 2969,2933, 1746, 1657, 1621, 1598, 1448, 1432, 1334, 1291, 1232, 1179, 1094,1001, 907, 881, 767, 756, 722 and 632 cm⁻¹;

(iii) an X-ray powder diffraction pattern comprising peaks at about 11.8°2θ, and about 13.0 °2θ;

herein designated as Form E.

In another embodiment, the invention relates to (−)-halofenate in acrystalline solid form, including a substantially pure form, whichprovides an X-ray powder diffraction pattern comprising peaks at about11.8 °2θ and about 13.0 °2θ; herein designated as Form E.

In yet another embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 11.8 °2θ, about 13.0 °2θ and an infrared spectrumcomprising at least one peak selected from about 3092 cm⁻¹, about 2871cm⁻¹, and about 1563 cm⁻¹; herein designated as Form E.

In a further embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 11.8 °2θ and about 13.0 °2θ, and a Raman spectrumcomprising at least one peak selected from about 2969 cm⁻¹, about 1746cm⁻¹, and about 1657 cm⁻¹; herein designated as Form E.

In an additional embodiment of the invention, the invention relates to(−)-halofenate in a crystalline solid form, including a substantiallypure form, which provides an x-ray powder diffraction pattern comprisingpeaks at about 11.8° 2θ, about 13.0° 2θ and an infrared spectrumcomprising at least one peak selected from about 3092 cm⁻¹, about 2871cm⁻¹, and about 1563 cm⁻¹, and a Raman spectrum comprising at least onepeak selected from about 2969 cm⁻¹, about 1746 cm⁻¹, and about 1657cm⁻¹; herein designated as Form E.

Further embodiments of the invention include the compound of(−)-halofenate in a crystalline solid Form A characterized by an X-raypowder diffraction pattern comprising a peak at about 10.8 °2θ and aninfrared spectrum comprising at least one peak selected from about 3322cm⁻¹ and about 2886 cm⁻¹; the compound of (−)-halofenate in acrystalline solid Form A characterized by a an X-ray powder diffractionpattern comprising a peak at about 10.8 °2θ, and a Raman spectrumcomprising at least one peak selected from about 3087 cm⁻¹ and about1663 cm⁻¹; and the compound of (−)-halofenate in a crystalline solidForm A characterized by an X-ray powder diffraction pattern comprising apeak at about 10.8 °2θ, an infrared spectrum comprising at least onepeak selected from about 3322 cm⁻¹ and about 2886 cm⁻¹, and a Ramanspectrum comprising at least one peak selected from about 3087 cm⁻¹ andabout 1663 cm⁻¹.

Form A can be generated in higher purity than forms B and C, and form Ais the most stable crystalline solid form. Taking these factors intoconsideration, an optimized crystallization process has been developedwherein (1) (−)-halofenate is dissolved in 6/1 heptane/isopropyl alcohol(2) the solution is seeded with crystals of (−)-halofenate (insoluble at30° C.), and (3) the solution is cooled and/or concentrated and the APIis isolated as crystalline solid form A. Implementation of this processreproducibly provides polymorph A with the level of any single impurity<0.2%.

After many trials it was unexpectedly discovered that when the slurry ofthe crude product was seeded with Form A, impurities were lowered to0.04 and 0.11%, respectively. The results are shown below in theExamples.

The optimized process uses a controlled manipulation of the crystallinesolid and amorphous forms of (−)-halofenate as the method for providingthe API with <0.2% of any single impurity and in the mostthermodynamically stable crystal form A.

In another embodiment of the present invention there is provided(−)-halofenate in a crystalline solid form A, including a substantiallypure form A, which is obtained by at least one of:

(i) heating (−)-halofenate in at least one solvent selected from thegroup consisting of heptane, 2-propanol, and combinations thereof;crystallizing at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent;(ii) drying a crystal of solid form B of (−)-halofenate;(iii) drying a crystal of solid form C of (−)-halofenate;(iv) heating (−)-halofenate in at least one solvent selected from thegroup consisting of heptane, 2-propanol, and combinations thereof;crystallizing in the presence of a crystal of a solid form of(−)-halofenate at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent; and(v) crystallizing (−)-halofenate from at least one solvent selected fromthe group consisting of acetonitrile, benzene, cyclohexanol, t-butylmethyl ether and combinations thereof and drying.

Furthermore, the present invention is directed to processes for thepreparation of solid forms A, B, C, D and E and an amorphous form. Thusin another embodiment, the invention relates to process for thepreparation of (−)-halofenate in a crystalline solid form A, including asubstantially pure form A, comprising at least one of:

(i) heating (−)-halofenate in at least one solvent selected from thegroup consisting of heptane, 2-propanol, and combinations thereof;crystallizing at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent;(ii) drying a crystal of solid form B of (−)-halofenate;(iii) drying a crystal of solid form C of (−)-halofenate;(iv) heating (−)-halofenate in at least one solvent selected from thegroup consisting of heptane, 2-propanol, and combinations thereof;crystallizing in the presence of a crystal of a solid form of(−)-halofenate at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent; and(v) crystallizing (−)-halofenate from at least one solvent selected fromthe group consisting of acetonitrile, benzene, cyclohexanol, t-butylmethyl ether and combinations thereof and drying.

In another embodiment of the present invention there is provided(−)-halofenate in a crystalline solid form B, including a substantiallypure form B, which is obtained by crystallizing (−)-halofenate from atleast one solvent selected from the group consisting of heptane,2-propanol, and combinations thereof and at a temperature of from about20° C. to −10° C. and drying until the crystals contain from about 2 toabout 3% solvent.

In another embodiment, the invention relates to process for thepreparation of (−)-halofenate in a crystalline solid form B, including asubstantially pure form B, comprising crystallizing (−)-halofenate fromat least one solvent selected from the group consisting of heptane,2-propanol, and combinations thereof and at a temperature of from about20° C. to −10° C. and drying until the crystals contain from about 2 toabout 3% solvent.

In another embodiment of the present invention there is provided(−)-halofenate in a crystalline solid form C, including a substantiallypure form C, which is obtained by crystallizing (−)-halofenate from atleast one solvent selected from the group consisting of heptane,2-propanol, and combinations thereof and at a temperature of from about50° C. to 0° C. and drying until the crystals contain about 0.05% toabout 0.3% solvent.

In another embodiment, the invention relates to process for thepreparation of (−)-halofenate in a crystalline solid form C, including asubstantially pure form C, comprising crystallizing (−)-halofenate fromat least one solvent selected from the group consisting of heptane,2-propanol, and combinations thereof and at a temperature of from about50° C. to 0° C. and drying until the crystals contain about 0.05% toabout 0.3% solvent.

In another embodiment of the present invention there is provided(−)-halofenate in a crystalline solid form D, including a substantiallypure form D, which is obtained by crystallizing (−)-halofenate from atleast one solvent selected from the group consisting of acetone,ethanol, dichloromethane and combinations thereof and drying.

In another embodiment, the invention relates to process for thepreparation of (−)-halofenate in a crystalline solid form D, including asubstantially pure form D, comprising crystallizing (−)-halofenate fromat least one solvent selected from the group consisting of acetone,ethanol, dichloromethane and combinations thereof and drying.

In another embodiment of the present invention there is provided(−)-halofenate in a crystalline solid form E, including a substantiallypure form E, which is obtained by crystallizing (−)-halofenate fromt-butyl methyl ether and heptane and drying.

In another embodiment, the invention relates to process for thepreparation of (−)-halofenate in a crystalline solid form E, including asubstantially pure form E, comprising crystallizing (−)-halofenate fromt-butyl methyl ether and heptane and drying.

In one embodiment, the invention relates (−)-halofenate in an amorphousform, including a substantially pure form.

In one embodiment, the invention relates (−)-halofenate in an amorphousform, including a substantially pure form, which provides an X-raypowder diffraction pattern substantially in accordance with FIG. 35.

In another embodiment, the invention relates (−)-halofenate in anamorphous form, including a substantially pure form, which provides anX-ray powder diffraction pattern comprising a broad peak substantiallybetween about 15 and about 30 °2θ.

In another embodiment of the present invention there is provided(−)-halofenate in an amorphous form, including a substantially pureform, obtained by heating (−)-halofenate in high humidity.

In another embodiment of the present invention there is provided(−)-halofenate in an amorphous form, including a substantially pureform, obtained by heating (−)-halofenate at greater than about 60° C.for at least about 3 weeks in at least about 74% humidity.

Accordingly in other embodiments, there is provided (−)-halofenate in anisolated form selected from the group consisting of crystalline solidform A, B, C, D, E and amorphous form. Within each of the aboveembodiments the compound is individually substantially pure form A, issubstantially pure form B, is substantially pure form C, issubstantially pure form D, is substantially pure form E or amorphousform.

In other embodiments, the invention relates to (−)-halofenate in asubstantially pure solid form consisting of greater than 91%(−)-halofenate and less than 9% of chemical impurities other than(−)-halofenate based on the total weight of (−)-halofenate. Within eachof the above embodiments, the compound in individual embodiments isgreater than 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99% by weight(−)-halofenate.

In another embodiment, the invention relates to (−)-halofenate in asubstantially pure solid form consisting of greater than 91%(−)-halofenate form A and less than 9% of other forms of (−)-halofenatebased on the total weight of (−)-halofenate. Within each of the aboveembodiments, the compound in individual embodiments is greater than 92%,93%, 94%, 95%, 96%, 97%, 98% and 99% of crystalline solid form A byweight of (−)-halofenate.

In another embodiment, the invention relates to (−)-halofenatesubstantially in a substantially pure solid form which is alsosubstantially free of the (+) isomer. In one embodiment the compound isgreater than 91% of the (−)-isomer and less than 9% of the (+) isomerbased on the total weight of halofenate. Within each of the aboveembodiments, the compound in individual embodiments is greater than 92%,93%, 94%, 95%, 96%, 97%, 98% and 99% of the (−) isomer by weight ofhalofenate.

In another embodiment the present invention provides a method ofenantiomerically enriching (−)-halofenate comprising heating(−)-halofenate in a solvent; crystallizing at a temperature of fromabout 50° C. to −10° C. and drying until the crystals contain less than0.05% solvent.

In another embodiment the present invention provides method provides(−)-halofenate in a solvent having an enantiomeric excess of at leastabout 95%.

A major advantage of these crystalline solid forms is that they are lesshygroscopic than the amorphous form. Therefore, the crystalline formscan be better handled and are more stable at normal environmentalhumidity levels. Because of its non-hygroscopic nature anhydrouscrystalline Form A retains a better physical appearance and handlingproperties over a longer period of time. An improvement in the physicalappearance of a dosage form of a drug enhances both physician andpatient acceptance and increases the likelihood of success of thetreatment.

Further embodiments of the invention include mixtures of the differentcrystalline solid forms, and the amorphous form, of (−) halofenate. Suchmixtures include compositions comprising at least one solid form or atleast two solid forms selected from Form A, Form B, Form C, Form D, FormE, and the amorphous form. Any of the analytical techniques describedherein may be used to detect the presence of the solid forms in suchcompositions. Detection may be done qualitatively, quantitatively, orsemi-quantitatively as those terms as used and understood by those ofskill in the solid-state analytical arts.

For these analyses, use of standard analytical techniques involvingreference standards may be used. Further, such methods may include useof techniques such as partial-lease squares in conjunction with adiffractive or spectroscopic analytical technique. These techniques mayalso be used in pharmaceutical compositions of the invention.

Because enantiomers have the same crystalline solid state properties,like X-ray and Raman data (see for example Z. Jane Li et al., J. Pharm.Sci., 1999, 88, pages 337-346) the above invention also relates to thecorresponding (+) enatiomer. For the purposes of the present invention,the above crystalline polymorphs and amorphous forms of the(−)-enantiomer are preferred.

(−)-Halofenate in a crystalline solid or amorphous form may be preparedby various methods as further described below in the Examples. Theexamples illustrate, but do not limit the scope of the presentinvention. (−)-Halofenate in crystalline solid or amorphous forms may beisolated using typical isolation and purification techniques known inthe art, including, for example, chromatographic, recrystallization andother crystallization procedures as well as modification of theprocedures outlined above.

III. Pharmaceutical Formulations and Methods of Administration

Besides being directed to different solid forms of (−) halofenate asdescribed herein which includes such forms in an isolated form, in otherembodiments there is provided a pharmaceutical composition comprising atherapeutically effective amount of (−)-halofenate of any of the aboveembodiments in admixture with at least one pharmaceutically acceptablecarrier or excipient.

The (−)-halofenate in a substantially pure crystalline solid and/oramorphic form may be used as single components or mixtures. For example,any combinations of Form A, Form B, Form C, Ford D, Form E, andamorphous form may be combined with at least one pharmaceuticallyacceptable carrier or excipient in a pharmaceutical composition.

As to pharmaceutical compositions of (−)-halofenate it is preferred thatthese contain 25-100% by weight, especially 50-100% by weight, of asubstantially pure form of (−)-halofenate of any of the aboveembodiments or combinations thereof, based on the total amount of(−)-halofenate. Preferably, such an amount of (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form is 75-100% byweight, especially 90-100% by weight. Highly preferred is an amount of95-100% by weight.

The invention further includes pharmaceutical compositions comprisingmixtures of therapeutic amounts of the solid forms of (−)-halofenatewhich are substantially free of its (+) stereoisomer. For example,therapeutically effective amounts of Form A together withtherapeutically effective amounts of at least one of Form B, Form C,Form D, Form E, and the amorphous form, each of which are substantiallyfree of their corresponding (+) stereoisomer could be combined togetherin a pharmaceutical composition which would then further include atleast one pharmaceutically acceptable carrier or excipient.

The invention also includes pharmaceutical compositions containingtherapeutically effective amounts of at least one solid form of(−)-halofenate substantially free of its corresponding (+) stereoisomertogether with at least one other solid form of (−)-halofenate,substantially free of its corresponding stereoisomer, in asub-therapeutic dose. Such a sub-therapeutic dose could include, forexample, a trace impurity of one of the other solid forms of(−)-halofenate. Such pharmaceutical compositions would further includeat least one pharmaceutically acceptable carrier or excipient.

Further embodiments of the invention include as follows.

A pharmaceutical composition comprising a therapeutically effectiveamount of (−) halofenate in crystalline solid Form A characterized by anX-ray Powder diffraction pattern comprising peaks at about 10.8 °2θ,about 22.0 °2θ, about 29.3 °2θ, and a Raman spectrum comprising at leastone peak selected from about 3087 cm⁻¹ and about 1663 cm⁻¹; and at leastone pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition comprising a therapeutically effectiveamount of (−) halofenate in crystalline solid Form B characterized by anX-ray Powder diffraction pattern comprising peaks at about 6.2° 2θ,about 12.4° 2θ, and at least one peak selected from about 18.8° 2θ,about 20.1° 2θ, and about 14.0° 2θ′ and least one pharmaceuticallyacceptable carrier or excipient.

A pharmaceutical composition comprising a therapeutically effectiveamount of (−) halofenate in crystalline solid Form C characterized by anX-ray Powder diffraction pattern comprising peaks at about 9.9 °2θ,about 13.3 °2θ, and at least one peak selected from about 15.5 °2θ,about 23.1 °2θ, about 14.7 °2θ, and about 25.9 °2θ; and at least onepharmaceutically acceptable carrier or excipient.

A pharmaceutical composition comprising a therapeutically effectiveamount of (−) halofenate in crystalline solid Form D characterized by anX-ray Powder diffraction pattern comprising peaks at about 9.6 °2θ andabout 17.4 °2θ, and a Raman spectrum comprising at least one peakselected from about 3077 cm⁻¹ and about 1329 cm⁻¹; and at least onepharmaceutically acceptable carrier or excipient.

A pharmaceutical composition comprising a therapeutically effectiveamount of (−) halofenate in crystalline solid Form E characterized by anX-ray Powder diffraction pattern comprising peaks at about 11.8° 2θ andabout 13.0° 2θ and a Raman spectrum comprising at least one peakselected from about 2969 cm⁻¹, about 1746 cm⁻¹, and about 1657 cm⁻¹; andat least one pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition comprising a therapeutically effectiveamount of (−) halofenate in an amorphous form characterized by a broadpeak between about 15° 2θ and about 30° 2θ; and at least onepharmaceutically acceptable carrier or excipient.

In the methods of the present invention, the (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form can bedelivered or administered to a mammal, e.g., a human patient or subject,alone, in the form of a pharmaceutically acceptable salt or hydrolyzableprecursor thereof, or in the form of a pharmaceutical composition wherethe compound is mixed with suitable carriers or excipient(s) in atherapeutically effective amount. By a “therapeutically effective dose”,“therapeutically effective amount”, or, interchangeably,“pharmacologically acceptable dose” or “pharmacologically acceptableamount”, it is meant that a sufficient amount of the compound of thepresent invention, alternatively, a combination, for example, a compoundof the present invention, which is substantially free of its (+)stereoisomer, and a pharmaceutically acceptable carrier, will be presentin order to achieve a desired result, e.g., alleviating a symptom orcomplication of Type 2 diabetes. In another example, more than one solidform of (−)halofenate substantially free of its (+) stereoisomer may beprepared in combination with a pharmaceutically acceptable carrier in asufficient amount to achieve a desired result, e.g., alleviating asymptom or complication of Type 2 diabetes.

The (−)-halofenate in at least one substantially pure crystalline solidand/or amorphic form that are used in the methods of the presentinvention can be incorporated into a variety of formulations fortherapeutic administration. More particularly, the (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form can beformulated into pharmaceutical compositions by combination withappropriate, pharmaceutically acceptable carriers or diluents, and canbe formulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, pills, powders, granules, dragees,gels, slurries, ointments, solutions, suppositories, injections,inhalants and aerosols. As such, administration of the (−)-halofenate inat least one substantially pure crystalline solid and/or amorphic formcan be achieved in various ways, including oral, buccal, rectal,parenteral, intraperitoneal, intradermal, transdermal, intratrachealadministration. Moreover, the (−)-halofenate in a substantially purecrystalline solid and/or amorphic form can be administered in a localrather than systemic manner, in a depot or sustained releaseformulation. In addition, the compounds can be administered in aliposome.

In addition, the (−)-halofenate in at least one substantially purecrystalline solid and/or amorphic form can be formulated with commonexcipients, diluents or carriers, and compressed into tablets, orformulated as elixirs or solutions for convenient oral administration,or administered by the intramuscular or intravenous routes. The(−)-halofenate in at least one substantially pure crystalline solidand/or amorphic form can be administered transdermally.

Further embodiments of the invention include pharmaceutical compositionsof (−) halofenate, including in therapeutically effective amounts ofForm A, and at least one of Form B, Form C, Form D, Form E, and theamorphous form. Said amounts of the at least one of Form B, Form C, FormD, Form E, and the amorphous form may or may not be in therapeuticallyeffective amounts. Such pharmaceutical compositions may be in the formof a solid oral composition such as a tablet or a capsule or as a drypowder for inhalation.

(−)-Halofenate in at least one substantially pure crystalline solidand/or amorphic form can be administered alone, in combination with eachother, or they can be used in combination with other known compoundsincluding other therapeutic agents (discussed supra). In pharmaceuticaldosage forms, the (−)-halofenate in at least one substantially purecrystalline solid and/or amorphic form can be administered in the formof their pharmaceutically acceptable salts thereof. They can containhydrolyzable moieties. They can also be used alone or in appropriateassociation, as well as in combination with, other pharmaceuticallyactive compounds.

Suitable formulations for use in the present invention are found inRemington's Pharmaceutical Sciences (Mack Publishing Company (1985)Philadelphia, Pa., 17th ed.), which is incorporated herein by reference.Moreover, for a brief review of methods for drug delivery, see, Langer,Science (1990) 249:1527-1533, which is incorporated herein by reference.The pharmaceutical compositions described herein can be manufactured ina manner that is known to those of skill in the art, i.e., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes. Thefollowing methods and excipients are merely exemplary and are in no waylimiting.

For injection, the (−)-halofenate in a substantially pure crystallinesolid and/or amorphic form can be formulated into preparations bydissolving, suspending or emulsifying them in an aqueous or nonaqueoussolvent, such as vegetable or other similar oils, synthetic aliphaticacid glycerides, esters of higher aliphatic acids or propylene glycol;and if desired, with conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives. Preferably, the (−)-halofenate in a substantially purecrystalline solid and/or amorphic form of the present invention can beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks's solution, Ringer's solution, orphysiological saline buffer. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

For oral administration, the (−)-halofenate in a substantially purecrystalline solid and/or amorphic form can be formulated readily bycombining with pharmaceutically acceptable carriers that are well knownin the art. Such carriers enable the (−)-halofenate in a substantiallypure crystalline solid and/or amorphic form to be formulated as tablets,pills, dragees, capsules, emulsions, lipophilic and hydrophilicsuspensions, liquids, gels, syrups, slurries, suspensions and the like,for oral ingestion by a patient to be treated. Pharmaceuticalpreparations for oral use can be obtained by mixing the (−)-halofenatein a substantially pure crystalline solid and/or amorphic form with asolid excipient, optionally grinding a resulting mixture, and processingthe mixture of granules, after adding suitable auxiliaries, if desired,to obtain tablets or dragee cores. Suitable excipients are, inparticular, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as, for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents can be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent dose combinations of (−)-halofenate in a substantially purecrystalline solid and/or amorphic form.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas, or from propellant-free, dry-powder inhalers. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The (−)-halofenate in a substantially pure crystalline solid and/oramorphic form can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection can be presented in unit dosage form, e.g., in ampules orin multidose containers, with an added preservative. The compositionscan take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and can contain formulator agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the (−)-halofenate in a substantially purecrystalline solid and/or amorphic form in water-soluble form.Additionally, suspensions of the (−)-halofenate in a substantially purecrystalline solid and/or amorphic form can be prepared as appropriateoily injection suspensions. Suitable lipophilic solvents or vehiclesinclude fatty oils such as sesame oil, or synthetic fatty acid esters,such as ethyl oleate or triglycerides, or liposomes. Aqueous injectionsuspensions can contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension can also contain suitablestabilizers or agents which increase the solubility of the(−)-halofenate in a substantially pure crystalline solid and/or amorphicform to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The (−)-halofenate in a substantially pure crystalline solid and/oramorphic form can also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, carbowaxes, polyethylene glycolsor other glycerides, all of which melt at body temperature, yet aresolidified at room temperature.

In addition to the formulations described previously, the (−)-halofenatein a substantially pure crystalline solid and/or amorphic form can alsobe formulated as a depot preparation. Such long acting formulations canbe administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds can be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. In apresently preferred embodiment, long-circulating, i.e., stealth,liposomes can be employed. Such liposomes are generally described inWoodle, et al., U.S. Pat. No. 5,013,556, the teaching of which is herebyincorporated by reference. The (−)-halofenate in a substantially purecrystalline solid and/or amorphic form of the present invention can alsobe administered by controlled release means and/or delivery devices suchas those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719; the disclosures of which are herebyincorporated by reference.

Certain organic solvents such as dimethylsulfoxide (DMSO) also can beemployed, although usually at the cost of greater toxicity.Additionally, the (−)-halofenate in a substantially pure crystallinesolid and/or amorphic form can be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various types of sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules can, depending on their chemicalnature, release the compounds for a few hours up to over 100 days.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in atherapeutically effective amount. The amount of composition administeredwill, of course, be dependent on the subject being treated, on thesubject's weight, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.Determination of an effective amount is well within the capability ofthose skilled in the art, especially in light of the detailed disclosureprovided herein.

For any of the (−)-halofenate in a substantially pure crystalline solidand/or amorphic form used in the method of the present invention, atherapeutically effective dose can be estimated initially from cellculture assays or animal models.

Moreover, toxicity and therapeutic efficacy of the (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form describedherein can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., by determining the LD₅₀, (thedose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween toxic and therapeutic effect is the therapeutic index and can beexpressed as the ratio between LD₅₀ and ED₅₀. (−)-Halofenate in asubstantially pure crystalline solid and/or amorphic form which exhibithigh therapeutic indices are preferred. The data obtained from thesecell culture assays and animal studies can be used in formulating adosage range that is not toxic for use in human. The dosage of such(−)-halofenate in a substantially pure crystalline solid and/or amorphicform lies preferably within a range of circulating concentrations thatinclude the ED₅₀ with little or no toxicity. The dosage can vary withinthis range depending upon the dosage form employed and the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition (see, e.g., Fingl et al. 1975 In: ThePharmacological Basis of Therapeutics, Ch. 1).

The amount of (−)-halofenate in a substantially pure crystalline solidand/or amorphic form that can be combined with a carrier material toproduce a single dosage form will vary depending upon the diseasetreated, the mammalian species, and the particular mode ofadministration. However, as a general guide, suitable unit doses for the(−)-halofenate in a substantially pure crystalline solid and/or amorphicform of the present invention can, for example, preferably containbetween 100 mg to about 3000 mg of the active compound. A preferred unitdose is between 500 mg to about 1500 mg. A more preferred unit dose isbetween 500 to about 1000 mg. Such unit doses can be administered morethan once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably1 or 2 times per day, so that the total daily dosage for a 70 kg adultis in the range of 0.1 to about 250 mg per kg weight of subject peradministration. A preferred dosage is 5 to about 250 mg per kg weight ofsubject per administration, and such therapy can extend for a number ofweeks or months, and in some cases, years. It will be understood,however, that the specific dose level for any particular patient willdepend on a variety of factors including the activity of the specificform of the (−)-halofenate employed; the age, body weight, generalhealth, sex and diet of the individual being treated; the time and routeof administration; the rate of excretion; other drugs which havepreviously been administered; and the severity of the particular diseaseundergoing therapy, as is well understood by those of skill in the area.

A typical dosage can be one 10 to about 1500 mg tablet taken once a day,or, multiple times per day, or one time-release capsule or tablet takenonce a day and containing a proportionally higher content of activeingredient. The time-release effect can be obtained by capsule materialsthat dissolve at different pH values, by capsules that release slowly byosmotic pressure, or by any other known means of controlled release.

It can be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

IV. Methods of Treatment A. Modulating Insulin Resistance, Type 2Diabetes and Hyperlipidemia

In another embodiment, the present invention encompasses a method ofmodulating insulin resistance in a mammal, the method comprisingadministering to the mammal a therapeutically effective amount of(−)-halofenate in a substantially pure crystalline solid and/oramorphous form. The method avoids the adverse effects associated withthe administration of a racemic mixture of halofenate by providing anenriched amount of the (−) stereoisomer of halofenate in a crystallinesolid or amorphous form which is insufficient to cause the adverseeffects associated with the inhibition of cytochrome P450 2C9.

The present invention also encompasses a method of modulating Type 2diabetes in a mammal, the method comprising administering to the mammala therapeutically effective amount of (−)-halofenate in a substantiallypure crystalline solid and/or amorphous form. The method avoids theadverse effects associated with the administration of a racemic mixtureof halofenate by providing an enriched amount of the (−) stereoisomer ofhalofenate in a crystalline solid or amorphous form which isinsufficient to cause the adverse effects associated with the inhibitionof cytochrome P450 2C9.

The present invention further encompasses a method of modulatinghyperlipidemia in a mammal, the method comprising administering to themammal a therapeutically effective amount of a (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form. The methodavoids the adverse effects associated with the administration of aracemic mixture of halofenate by providing an enriched amount of the (−)stereoisomer of halofenate in a crystalline solid or amorphous formwhich is insufficient to cause the adverse effects associated with theinhibition of cytochrome P450 2C9.

The racemic mixture of halofenate (i.e., a 1:1 racemic mixture of thetwo enantiomers) possesses antihyperlipidemic activity and providestherapy and a reduction of hyperglycemia related to diabetes whencombined with certain other drugs commonly used to treat this disease.However, this racemic mixture, while offering the expectation ofefficacy, causes adverse effects. The term “adverse effects” includes,but is not limited to, nausea, gastrointestinal ulcers, andgastrointestinal bleeding. Other side effects that have been reportedwith racemic halofenate include potential problems with drug-druginteractions, especially including difficulties controllinganticoagulation with COUMADIN™. Utilizing substantially pure compoundsof the present invention results in clearer dose related definitions ofefficacy, diminished adverse effects, and accordingly, an improvedtherapeutic index. As such, it has now been discovered that it is moredesirable and advantageous to administer the (−) enantiomer ofhalofenate instead of racemic halofenate.

B. Combination Therapy with Additional Active Agents

The compositions can be formulated and administered in the same manneras detailed below. “Formulation” is defined as a pharmaceuticalpreparation that contains a mixture of various excipients and keyingredients that provide a relatively stable, desirable and useful formof a compound or drug. For the present invention, “formulation” isincluded within the meaning of the term “composition.” The(−)-halofenate in a substantially pure crystalline solid and/or amorphicform of the present invention can be used effectively alone or incombination with one or more additional active agents depending on thedesired target therapy (see, e.g., Turner, N. et al. Prog. Drug Res.(1998) 51: 33-94; Haffner, S. Diabetes Care (1998) 21: 160-178; andDeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Anumber of studies have investigated the benefits of combinationtherapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol.Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes StudyGroup: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, C. W., (ed.),CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6^(th) Edition(Mosby—Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann.Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin. Ther. (1997)19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; andIwamoto, Y. et al, Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am.J. Cardiol (1998) 82(12A): 3U-17U). These studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Combination therapy includesadministration of a single pharmaceutical dosage formulation whichcontains (−)-halofenate in a substantially pure crystalline solid and/oramorphic form and one or more additional active agents, as well asadministration of (−)-halofenate in a substantially pure crystallinesolid and/or amorphic form and each active agent in its own separatepharmaceutical dosage formulation. For example, a (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form and an HMG-CoAreductase inhibitor can be administered to the human subject together ina single oral dosage composition, such as a tablet or capsule, or eachagent can be administered in separate oral dosage formulations. Whereseparate dosage formulations are used, (−)-halofenate in a substantiallypure crystalline solid and/or amorphic form and one or more additionalactive agents can be administered at essentially the same time (i.e.,concurrently), or at separately staggered times (i.e., sequentially).Combination therapy is understood to include all these regimens.

An example of combination therapy that modulates (prevents the onset ofthe symptoms or complications associated) atherosclerosis, wherein(−)-halofenate in a substantially pure crystalline solid and/or amorphicform is administered in combination with one or more of the followingactive agents: an antihyperlipidemic agent; a plasma HDL-raising agent;an antihypercholesterolemic agent, such as a cholesterol biosynthesisinhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase inhibitor(also referred to as statins, such as lovastatin, simvastatin,pravastatin, fluvastatin, and atorvastatin), an HMG-CoA synthaseinhibitor, a squalene epoxidase inhibitor, or a squalene synthetaseinhibitor (also known as squalene synthase inhibitor); an acyl-coenzymeA cholesterol acyltransferase (ACAT) inhibitor, such as melinamide;probucol; nicotinic acid and the salts thereof and niacinamide; acholesterol absorption inhibitor, such as β-sitosterol; a bile acidsequestrant anion exchange resin, such as cholestyramine, colestipol ordialkylaminoalkyl derivatives of a cross-linked dextran; an LDL (lowdensity lipoprotein) receptor inducer; fibrates, such as clofibrate,bezafibrate, fenofibrate, and gemfibrizol; vitamin B₆ (also known aspyridoxine) and the pharmaceutically acceptable salts thereof, such asthe HCl salt; vitamin B₁₂ (also known as cyanocobalamin); vitamin B₃(also known as nicotinic acid and niacinamide, supra); anti-oxidantvitamins, such as vitamin C and E and beta carotene; a beta-blocker; anangiotensin II antagonist; an angiotensin converting enzyme inhibitor;and a platelet aggregation inhibitor, such as fibrinogen receptorantagonists (i.e., glycoprotein IIb/IIIa fibrinogen receptorantagonists) and aspirin. As noted above, the (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form can beadministered in combination with more than one additional active agent,for example, a combination of (−)-halofenate in a substantially purecrystalline solid and/or amorphic form with an HMG-CoA reductaseinhibitor (e.g., lovastatin, simvastatin and pravastatin) and aspirin,or (−)-halofenate in a substantially pure crystalline solid and/oramorphic form with an HMG-CoA reductase inhibitor and a β-blocker.

Another example of combination therapy can be seen in treating obesityor obesity-related disorders, wherein the (−)-halofenate in asubstantially pure crystalline solid and/or amorphic form can beeffectively used in combination with, for example, phenylpropanolamine,phentermine, diethylpropion, mazindol; fenfluramine, dexfenfluramine,phentiramine, β₃ adrenoceptor agonist agents; sibutramine,gastrointestinal lipase inhibitors (such as orlistat), and leptins.Other agents used in treating obesity or obesity-related disorderswherein the (−)-halofenate in a substantially pure crystalline solidand/or amorphic form can be effectively used in combination with, forexample, neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin,histamine H₃ receptors, dopamine D₂ receptors, melanocyte stimulatinghormone, corticotrophin releasing factor, galanin and gamma aminobutyric acid (GABA).

Still another example of combination therapy can be seen in modulatingdiabetes (or treating diabetes and its related symptoms, complications,and disorders), wherein the (−)-halofenate in a substantially purecrystalline solid and/or amorphic form can be effectively used incombination with, for example, sulfonylureas (such as chlorpropamide,tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase,glimepiride, and glipizide), biguanides (such as metformin),thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, androsiglitazone) and other insulin sensitizers (such as Muraglitazar,AMG-131/T-131, tesaglitazar, DRF-10945, AZD-4619, E-3030, GSK-677954,GW-501516, GW-590735, R-483, KRP-101, GSK-641597, LY-674, LY-929,naveglitazar, netoglitazone, MBX-2044, NS-220, LBM-642, NO-5129, PLX-204and M-24); dehydroepiandrosterone (also referred to as DHEA or itsconjugated sulphate ester, DHEA-SO₄); antiglucocorticoids; TNFαinhibitors; α-glucosidase inhibitors (such as acarbose, miglitol, andvoglibose), pramlintide (a synthetic analog of the human hormoneamylin), other insulin secretogogues (such as repaglinide, gliquidone,and nateglinide), insulin, as well as the active agents discussed abovefor treating atherosclerosis.

A further example of combination therapy can be seen in modulatinghyperlipidemia (treating hyperlipidemia and its related complications),wherein the (−)-halofenate in a substantially pure crystalline solidand/or amorphic form can be effectively used in combination with, forexample, statins (such as fluvastatin, lovastatin, pravastatin orsimvastatin), bile acid-binding resins (such as colestipol orcholestyramine), nicotinic acid, probucol, betacarotene, vitamin E, orvitamin C.

In accordance with the present invention, a therapeutically effectiveamount of a (−)-halofenate in a substantially pure crystalline solidand/or amorphic form can be used for the preparation of a pharmaceuticalcomposition useful for treating diabetes, treating hyperlipidemia,treating obesity, lowering triglyceride levels, lowering cholesterollevels, raising the plasma level of high density lipoprotein, and fortreating, preventing or reducing the risk of developing atherosclerosis.

Additionally, an effective amount of (−)-halofenate in a substantiallypure crystalline solid and/or amorphic form and a therapeuticallyeffective amount of one or more active agents selected from the groupconsisting of: an antihyperlipidemic agent; a plasma HDL-raising agent;an antihypercholesterolemic agent, such as a cholesterol biosynthesisinhibitor, for example, an HMG-CoA reductase inhibitor, an HMG-CoAsynthase inhibitor, a squalene epoxidase inhibitor, or a squalenesynthetase inhibitor (also known as squalene synthase inhibitor); anacyl-coenzyme A cholesterol acyltransferase inhibitor; probucol;nicotinic acid and the salts thereof; niacinamide; a cholesterolabsorption inhibitor; a bile acid sequestrant anion exchange resin; alow density lipoprotein receptor inducer; clofibrate, fenofibrate, andgemfibrozil; vitamin B₆ and the pharmaceutically acceptable saltsthereof; vitamin B₁₂; an anti-oxidant vitamin; a β-blocker; anangiotensin II antagonist; an angiotensin converting enzyme inhibitor; aplatelet aggregation inhibitor; a fibrinogen receptor antagonist;aspirin; phentiramines, β₃ adrenergic receptor agonists; sulfonylureas,biguanides, α-glucosidase inhibitors, other insulin secretogogues, andinsulin can be used together for the preparation of a pharmaceuticalcomposition useful for the above-described treatments.

In addition, the present invention provides for kits with unit doses of(−)-halofenate in a substantially pure crystalline solid and/or amorphicform either in oral or injectable doses. In addition to the containerscontaining the unit doses will be an informational package insertdescribing the use and attendant benefits of the drugs in alleviatingsymptoms and/or complications associated with Type 2 diabetes as well asin alleviating hyperlipidemia. Preferred compounds and unit doses arethose described herein above.

It should be understood that the foregoing discussion, embodiments andexamples merely present a detailed description of certain preferredembodiments and are in no way limiting. It will be apparent to those ofordinary skill in the art that various modifications and equivalents canbe made without departing from the spirit and scope of the invention.All the patents, journal articles and other documents discussed or citedabove are herein incorporated by reference.

V. Examples

The (−)-halofenate in a substantially pure crystalline solid and/oramorphic form of the present invention can be readily prepared using theprocesses set forth from the following examples which are illustrative.

A. Instrumental 1. X-ray Powder Diffraction

X-ray powder diffraction (XRPD) analyses were performed using either aShimadzu) (RD-6000 X-ray powder diffractometer or an Inel XRG-3000diffractometer. The Shimadzu XRD-6000 X-ray powder diffractometer usedCu Kα radiation, and is equipped with a long fine focus x-ray tube. Thetube voltage and amperage were set to 40 kV and 40 mA, respectively. Thedivergence and scattering slits were set at 1° and the receiving slitwas set at 0.15 mm. Diffracted radiation was detected by a NaIscintillation detector. A theta-two theta continuous scan at 3°/min (0.4sec/0.02° step) from 2.5 to 40 °2θ was used. A silicon standard wasanalyzed to check the instrument alignment. Data were collected andanalyzed using XRD-6000 v. 4.1. Samples were prepared for analysis byplacing them in an aluminum holder with a silicon insert.

A Bragg-Brentano instrument like the Shimadzu system used formeasurements reported herein, a systematic peak shift (all peaks areshifted in the same direction by a same degree) in °2θ can result fromsample preparation errors as described in Chen et al.; J Pharmaceuticaland Biomedical Analysis, 2001; 26, 63. This systematic peak shift canoccur in the range of up to about 0.2 °2θ.

The Inel XRG-3000 diffractometer is equipped with a CPS (Curved PositionSensitive) detector with a 2θ range of 120°. Real time data werecollected using Cu-Kα radiation starting at approximately 4 °2θ at aresolution of 0.03 °2θ. The tube voltage and amperage were set to 40 kVand 30 mA, respectively. The pattern is displayed from 2.5-40 °2θ.Samples were prepared for analysis by packing them into thin-walledglass capillaries. Each capillary was mounted onto a goniometer headthat is motorized to permit spinning of the capillary during dataacquisition. The samples were analyzed for 5 or 10 min. Instrumentcalibration was performed using a silicon reference standard.

2. Thermal Analysis

Differential scanning calorimetry (DSC) was performed using a TAInstruments 2920 differential scanning calorimeter. The sample wasplaced into an aluminum DSC pan and the weight accurately recorded. Thepan was covered with a lid and then crimped. The sample cell wasequilibrated at 25° C. and heated under a nitrogen purge at a rate of10° C./min, up to a final temperature of 350° C. Indium metal was usedas the calibration standard. Reported temperatures are at the transitionmaxima.

Thermographic analyses (TGA) was performed using a TA Instruments 2920thermographic analyzer. The sample was placed into an aluminum samplepan and inserted into a TGA furnace. The sample was first equilibratedat 25° C., then heated under a nitrogen at a rate of 10° C./min, up to afinal temperature of 350° C. Nickel and ALUMEL™ were used as calibrationstandards.

3. Cyclic DSC

Cyclic differential scanning calorimetry (DSC) was performed using a TAInstruments 2920 differential scanning calorimeter. The sample wasplaced into an aluminum DSC pan and the weight accurately recorded. Thepan was covered with a lid and then crimped. The method was as follows:

1. Ramp 10° C./min. to 90° C.

2. Isothermal for 15 min.

3. Equilibrate at −50° C.

4. Isothermal for 5 min.

5. Ramp 10° C./min. to 140 or 200° C.

Indium metal was used as the calibration standard. Reported temperaturesare at the transition maxima.

4. Hot Stage Microscopy

Hot stage microscopy was performed using a Linkam hot stage (model FTIR600) mounted on a Leica DM LP microscope. Samples were observed at amagnification range of 100× to 400× with a lambda plate with crossedpolarizers. Samples were placed on a coverslip and a drop of siliconoil. Another coverslip was then placed over the sample. Each sample wasvisually observed as the stage was heated. Images were captured for someof the samples. The hot stage was calibrated using USP melting pointstandards.

5. Optical Microscopy

Optical microscopy was performed using a Wolfe polarizing microscopewhen no images were captured. Samples observed at a magnification rangeof 20× to 40× with and without cross polarizers. Samples were placed ona glass slide or viewed within the vial. For captured images, polarizedlight microscopy was performed using a Leica DM LP microscope. Sampleswere observed at a magnification range of 50× to 400× with a lambdaplate with crossed polarizers. Samples were placed on a glass slide.

6. Infrared Spectroscopy

Infrared spectra were acquired on a MAGNA-IR 860® Fourier transforminfrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with anextended range potassium bromide (KBr) beamsplitter, and a deuteratedtriglycine sulfate (DTGS) detector. A diffuse reflectance accessory (THECOLLECTOR™, Thermo Spectra-Tech) was used for sampling. Each spectrumrepresents 128 co-added scans collected at a spectral resolution of4.000 cm⁻¹. Sample preparation consisted of placing the sample into a 3or 13-mm diameter cup. A background data set was acquired with analignment mirror in place. A Log 1/R (R=reflectance) spectrum wasacquired by taking a ratio of these two data sets against each other.Wavelength calibration was performed using polystyrene.

7. Raman Spectroscopy

FT-Raman spectra were acquired on an FT-Raman 960 spectrometer (ThermoNicolet). This spectrometer uses an excitation wavelength of 1064 nm.Approximately 1.011 W of Nd:YVO₄ laser power was used to irradiate thesample. The Raman spectra were prepared for analysis by palacing thematerial in a glass tube and positioning the tube in a gold-coated tubeholder in the accessory, or placing the sample into a gold-coatedcapillary holder. A total of 256 sample scans were collected from3600-98 cm⁻¹ at a spectral resolution of 4.000 cm⁻¹, using Happ-Genzelapodization. Wavelength calibration was performed using sulfur andcyclohexane.

8. NMR Spectroscopy

Solution ¹H NMR spectra were acquired for the as-received material atambient temperature on a Bruker Instruments AM-250 spectrometer at amagnetic field strength of 5.87 Tesla (¹H Larmor frequency=250 MHz). Thesample was prepared by dissolving 0.7-0.8 mg sample in ca. 0.5 mL ofNMR-grade DMSO-d₆. Spectra were acquired with a 1H pulse width of 7.5 μsa 2.34 second acquisition time, a 5 second delay between scans, aspectral width of 3496.5 Hz with 16384 data points, and 128 transients.Each free indication decay (FID) was processed with GRAMS/32 AI softwarev. 6.00 using a Fourier number equal to twice the number of acquiredpoints with an exponential line broadening factor of 0.43 Hz to improvesensitivity. Peak tables were generated by the GRAMS software peakpicking algorithm. Spectra were referenced to internal TMS at 0.0 ppm.

9. Automated Moisture Sorption/Desorption

Moisture sorption/desorption data were collected on a VTI-SGA-100 VaporSorption Analyzer. Sorption and desorption data were collected over arange of 5% to 95% relative humidity (RH) at 10% RH intervals under anitrogen purge. Samples were not dried prior to analysis. Equilibriumcriteria used for analysis were less than 0.0100% weight change in 5minutes with a maximum equilibration time of 3 hours if the weightcriterion was not met. Data were not corrected for the initial moisturecontent of the samples. Sodium chloride and polyvinylpyrolidone wereused as calibration standards. A sample was taken after desorption wascomplete and analyzed by powder X-ray diffraction for potential formchange.

B. Preparation Methods for Forms A, B, C, D, E, and Amorphous Example 1Crystallization of (−)-Halofenate Form A

Method i.

A 100-mL bottom-drain reactor was charged with 2.62 g of (−)-halofenate(94.2% ee) and 26.2 g of 6/1 (v/v) heptane/2-propanol. The mixture washeated to 39° C. to give a solution, then cooled to 10° C. at a rate of1° C./min to give a slurry; the slurry was heated to obtain a lightslurry at 23° C. The light slurry was cooled to 6.2° C. at a rate of0.05° C./min and held for about 10 hours before the solid was isolatedby vacuum filtration. Vacuum oven drying at room temperature afforded1.57 g (60% recovery, 99.76% ee) of (−)-halofenate Form B containingabout 2-3% heptane. Further vacuum oven drying at about 50° C. affordedForm C containing heptane, but at a concentration of about 0.3%. Furthervacuum oven drying at about 50° C. afforded Form A containing no morethan about 0.05% heptane.

Method ii.

(−)-halofenate form B was heated to melting and allowed to cool atambient conditions to afford Form A.

Method iii.

(−)-halofenate form C was heated to melting and allowed to cool atambient conditions to afford Form A.

Method iv.

A 200-mL, glass-jacketed vessel with a Teflon, bottom plug-valve was setup with a three-bladed impeller (pitched for down-flow pumping) and ahastelloy thermocouple. The crystallizer vessel head was also equippedwith a condenser having a nitrogen bubbler atop. (−)-Halofenate (4.5 g,dried) and solvent [46.8 g of n-heptane (Phillips Pure Grade):2-propanol (Fisher HPLC Grade), 6:1, v:v] were added to a 100-mL,one-necked flask with a magnetic stirring bar. A condenser was placed inthe neck and the flask was heated to a solution in a water bath at about50° C. The solution was filtered through a 0.5 mm PTFE filter on a HPLCsolvent filtration apparatus. The filtrate was poured to thecrystallizer vessel and totaled 49.6 g. The amount of solute in thesolution which was lost to the dissolution/filtration equipment wasestimated at 0.15 g. The solution was cooled to 30° C. and seed with0.0303 g of (−)-halofenate (Form A). The contents were stirred at 275rpm and cooled by setting the jacket setpoint to 27° C. Additionalnucleation was observed during cool-down at 28° C., 13 minutes afterseeding. A thicker slurry developed over about 1.5 hours at 27° C. Thesuspension was heated to 28° C., held for 0.75 hours, and then cooledusing the following jacket profile: from 28 to 20° C. at 0.833° C./hour,from 20 to 8° C. at 2.40° C./hour, from 8 to −6° C. at 3.50° C./hour.The slurry was held for 5 hours at −6° C. before isolation by suctionfiltration on a 60-mL, C-fritted, glass funnel. The mother liquor (38.32g) was clear and colorless. Chilled n-heptane (13.8 g) was added to thevessel as a rinse and top-loaded to the wetcake. The wash was combinedwith the previous mother liquor and totaled 51.94 g. The washed wetcake(5.62 g) was transferred to a dish and dried in a vacuum oven for 19hours at room temperature. The dry product (3.42 g, 78.6% isolatedyield) was analyzed by XRD and matched the pattern of the Form A crystalstructure. By HPLC, (+)-halofenate was not detected in the crystalproduct. By NMR, the product contained 0.04% heptane. The mother liquorand wash solution contained about 0.079% (+)-halofenate and 1.39%(−)-halofenate.

Method v.

A 50-gallon glass-lined steel reactor equipped with a 12″ diameter3-bladed retreat curve agitator was charged with 21 lb of crude(−)-halofenate, 177 lb of n-heptane and 34 lb of 2-propanol. The mixturewas heated to 48° C. to completely dissolve the (−)-halofenate. Thereactor solution was pressure transferred to a similarly equipped 100gallon glass-lined steel reactor through a 0.2 micron polish filter toremove any potential solid contaminants. The transfers typicallyrequired about 10 minutes. About 9 lb of n-heptane and 2 lb of2-propanol were loaded to a 50-gallon glass-lined steel reactor equippedwith a 12″ diameter 3-bladed retreat curve agitator. After heating to50° C., the solvent was pressure transferred to the 100-gallon reactorto flush the transfer line and filter. The 100-gallon reactor solutionwas cooled form 50° C. to 27° C. at 12° C./hr. The supersaturatedsolution was seeded with about 50 grams of (−)-halofenate. The seedcrystals were mixed with n-heptane and the resulting slurry was vacuumloaded through the reactor sample line. The 100-gallon reactor contentswere held at 27° C. until nucleation occurred. Typically a white slurrywas visible after about 30 minutes. The (−)-halofenate in 100-gallonreactor was crystallized by cooling. The typical jacket cooling profilewas: cool from 27 to 20° C. at 1° C./hr, 20 to 8° C. at 2.4° C./hr and 8to −8° C. at 3.5° C./hr. After holding the 100-gallon reactor slurrybelow −8° C. for 4 hours, the slurry was transferred to a 30″ diameter316 stainless steel centrifuge to isolate the product by centrifugationon a 1-3 micron polypropylene filter cloth. The reactor was rinsed with60 lb of n-heptane to remove any product still remaining in the reactor.Finally the wetcake was washed with 32 lb of chilled n-heptane throughthe centrifuge wash nozzles. About 33 lb of wetcake was unloaded formthe centrifuge (ca. 50% loss-on-drying). The wetcake was dried in eithera laboratory vacuum oven or a 3-cubic foot glass-lined tumble dryer at25° C. until the LOD was below 0.3%. The dry product was unloaded toline fiber packages through a 3 mesh wire screen.

Method vi.

Approximately 66 mg of (−)-halofenate was dissolved in approximately 2mL of acetonitrile. Approximately 1 mL of the solution was filteredusing a 0.2 μm nylon syringe filter into an open 20 mL scintillationvial. The solution was allowed to dry at ambient conditions in a fumehood to white solids.

Method vii.

Approximately 65 mg of (−)-halofenate was dissolved in 0.5 mL ofacetonitrile was filtered through a 0.2 μm nylon syringe filter. Added15 mL of water to the solution and vortexed briefly. A slightly cloudysolution was obtained. The solution was centrifuged for 5 minutes atambient temperature. A colorless solution with a small amount of solidwas produced. The solid was collected, dried in fume hood.

Method viii.

Approximately 60 mg of (−)-halofenate was dissolved in approximately 2mL of benzene. Approximately 1 mL of the solution was filtered using a0.2 μm nylon syringe filter into a 20 mL scintillation vial covered withan aluminum foil containing a pinhole. The solution was allowed to dryat ambient conditions in a fume hood to white solids.

Method ix.

Approximately 53 mg of (−)-halofenate was dissolved in approximately 2mL of cyclohexanol. Approximately 1 mL of the solution was filteredusing a 0.2 pin nylon syringe filter into an open 20 mL scintillationvia. Allowed to dry at ambient conditions in a fume hood to whitesolids.

Method x.

Approximately 51 mg of (−)-halofenate was dissolved in approximately 2mL tertiary-butyl methyl ether. Approximately 1 mL of the solution wasfiltered using a 0.2 μm nylon syringe filter into an open 20 mLscintillation via. Allowed to dry at ambient conditions in a fume hoodto white solids.

Method xi.

Approximately 97 mg of (−)-halofenate was dissolved in approximately 2mL of toluene. Approximately 1 mL of the solution was filtered using a0.2 μm nylon syringe filter into an open 20 mL scintillation vial.Allowed to dry at ambient conditions in a fume hood to white solids.

Example 2 Crystallization of (−)-Halofenate Form B

Method i.

A 100-mL bottom-drain reactor was charged with 2.62 g of (−)-halofenate(94.2% ee) and 26.2 g of 6/1 (v/v) heptane/2-propanol. The mixture washeated to 39° C. to give a solution, then cooled to 10° C. at a rate of1° C./min to give a slurry; the slurry was heated to obtain a lightslurry at 23° C. The light slurry was cooled to 6.2° C. at a rate of0.05° C./min and held for about 10 hours before the solid was isolatedby vacuum filtration. Vacuum oven drying at room temperature afforded1.57 g (60% recovery, 99.76% ee) of (−)-halofenate containing about 2-3%heptane.

Method ii.

Approximately 200 mg of (−)-halofenate was charge to a glass vial. 2.57mL heptane were pipetted to the vial, followed by 0.43 mL 2-propanol (3mL heptane/IPA 6:1, v:v). The sample was vortexed for a few minutes;much solid remained. The vial was then placed in a controlledtemperature bath (water/anti-freeze) at ca. 25° C. The temperature ofthe bath was raised in small increments to dissolve the entire solid.The sample was removed periodically for brief vortexing. At 40° C.,after more than 30 minutes, the entire solid had dissolved.

The resulting solution was hot-filtered into two clean glass vials. Bothvials were kept in the 40° C. bath for approximately 10 minutes toensure no precipitation of the solid from filtering. The temperature ofthe bath was slowly lowered to 18° C. After more than five and halfhours, the bath temperature reached 18° C., and one of the vials wasplaced in the freezer (ca. −20° C.). Neither sample appeared tocontaining any solid. The bath temperature was then raised to 25° C.After more than 15 minutes at 25° C., the second vial was placed in thesame freezer. This sample contained no solid upon entering the freezer.

After being stored overnight in the freezer both samples were thick withsolid. The samples were warmed to ambient, and the supernatant wasremoved. A small portion of each solid sample was transferred to a glassslide and analyzed by polarized light microscopy. The slide was storedunder ambient conditions and submitted for single crystal X-ray. Aportion of each of the vial samples was analyzed by Inel capillary XRPD;the capillaries were packed while the solids were wet.

The vials containing the remaining samples were left uncapped in thefume hood to air-dry the solids. The solids were dried approximately 5hours, and the vials were capped. The vials were left at ambient forabout a day. Approximately 12 mg of one of the samples was transferredto a clean vial and dried upon vacuum at ambient temperature for about 5hours. The vacuum-dried sample was analyzed by Inel capillary XRPD. theair-dried samples were move to the refrigerator (ca. 4° C.) for storage.

Method iii.

Approximately 200 mg of (−)-halofenate was dissolved in approximately2.5 mL of heptane and approximately 0.4 mL of 2-propanol. The sample washeated for approximately 50 minutes in a 40° C. water bath yielding aclear solution. Approximately half of the solution was then filteredwhile hot through a warm 0.2 μm nylon syringe filter. The filteredsolution was returned to the water bath and cooled to 18° C. forapproximately 4.5 hours. No precipitation observed. Sample wastransferred to a freezer at approximately −17° C. overnight. Sample wasremoved from freezer and decanted supernatant off as solution warmed toambient temperature to recover white solids.

Example 3 Crystallization of (−)-Halofenate Form C

A 100-mL bottom-drain reactor was charged with 2.62 g of (−)-halofenate(94.2% ee) and 26.2 g of 6/1 (v/v) heptane/2-propanol. The mixture washeated to 39° C. to give a solution, then cooled to 10° C. at a rate of1° C./min to give a slurry; the slurry was heated to obtain a lightslurry at 23° C. The light slurry was cooled to 6.2° C. at a rate of0.05° C./min and held for about 10 hours before the solid was isolatedby vacuum filtration. Vacuum oven drying at room temperature afforded1.57 g (60% recovery, 99.76% ee) of (−)-halofenate containing about 2-3%heptane. Further vacuum oven drying at about 50° C. afforded Form Ccontaining heptane, but at a concentration of at about 0.3%.

Example 4 Crystallization of (−)-Halofenate Form D

Method i.

Approximately 52 mg of (−)-halofenate was dissolved in approximately in1 mL of acetone. The solution was filtered using a 0.2 μm nylon syringefilter and the filtered solution was rotary evaporated. The resultingsample was dried under vacuum at ambient temperature to give whitesolids.

Method ii.

Approximately 59 of mg of (−)-halofenate was dissolved in approximately2 mL of ethanol. Approximately 1 mL of the solution was filtered using a0.2 μm nylon syringe filter into an open 20 mL scintillation vial.Allowed to dry at ambient conditions in a fume hood to white solids.

Example 5 Crystallization of (−)-Halofenate Form E

Approximately 60 mg of (−)-halofenate was dissolved in 0.5 mL oftertiary-butyl methyl ether. The solution was filtered using a 0.2 μmnylon syringe filter into 40 mL of cold heptane cooled in a dryice/acetone bath and capped. Solution became cloudy and solids formedafter approximately an hour. The solid was recovered by pouring out thesolution. The sample was vacuum dried at ambient temperature to yieldwhite powder.

Example 6 Preparation of Amorphous (−)-Halofenate

Approximately 114 mg of (−)-halofenate was chopped to a fine powder andplaced in an open vial. The vial was placed into a jar containing asaturated salt solution at approximately 74% relative humidity andplaced it an oven at 60° C. for 3 weeks. The sample becameclear/colorless liquid that quickly converted into a clear to off-whitegel when removed from the jar. The off-white gel was amorphous.

Example 7 Slurry Interconversion Studies

Samples of mixed forms by XRPD and pure forms were used forinterconversion studies (see FIG. 37).

A saturated solution was prepared by vortexing and sonicating ca. 4 mg(−)-halofenate Form A in approximately 5-6 mL cyclohexane. This solutionwas filtered into a sample containing a mixture of ca. 40 mg Form A/FormD. The mixture was slurred on a rotating wheel at ambient temperaturefor approximately 6 days. The solids were recovered by vacuum filtrationand vacuum dried at ambient temperature. The dry solids were analyzed bypolarized light microscopy and XRPD.

The experiment was repeated using a shaker block at ca 50° C. using 2 mLof cyclohexane and slurried for ca. 3 days. and the supernatant wasremoved through decantation. Both the ambient and 50° C. experimentswere repeated using pure forms A and E (ca. 20 mg of each form). Theambient experiment was also repeated with A, B, D, and E (ca. 10 mg ofeach form, slurred approximately 7 days) on a rotating wheel and on amagnetic stir plate in the refrigerator (ca 5° C.). When conversion wasnot deemed complete by XRPD solids were re-slurried in cyclohexane.

Interconversion studies were carried out in cyclohexane at ambienttemperature 50° C. and 5° C. (see FIG. 37). The solvent was chosenbecause of the high solubility of the various forms in common organicsolvents. Forms A, B, D and E were used as starting materials. Allslurries resulted in Form A. This confirms that Form A is the moststable crystal form of (−)-halofenate.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference.

What is claimed is:
 1. A compound of (−) halofenate in a crystallinesolid form A characterized by: (i) an X-ray powder diffraction patterncomprising a peak at 10.8 °2θ, 22.0 °2Θ, and 29.3 °2Θ; (ii) an infraredspectrum comprising a peak at 3479, 3322, 3032, 2958, 2886, 1918, 1850,1753, 1651, 1340, 1017 and 884; and (iv) a DSC maximum endotherm atabout 80° C.; wherein the crystalline solid form A is at least 99.5% byweight of (−)-halofenate and 0.5% by weight or less of other non-solventcompounds.
 2. The compound of claim 1 wherein the compound consists ofgreater than 95% (−)-halofenate form A and less than 5% of othernon-solvent compounds.
 3. A compound that is (−)-halofenate in acrystalline solid form A characterized by: (i) an infra red spectrumcomprising absorption peaks at 3479, 3322, 3082, 2842, 2358, 1918, 1753,1651, 1548, 1340 and 1017 cm⁻¹; (ii) a Raman spectrum comprisingabsorption peaks at 3087, 3071, 2959, 2933, 1747, 1598, 1333, 1095,1001, 757, 723 and 631 cm⁻¹; (iii) an X-ray powder diffraction patterncomprising peaks at 10.8 °2θ and 22.0 °2 θ, and 29.3 °2θ; and (iv) a DSCmaximum endotherm at 80° C.; wherein the crystalline solid form A is atleast 99.5% by weight of (−)-halofenate and 0.5% by weight or less ofother non-solvent compounds.
 4. The compound of claim 3 furthercharacterized by: an infra red spectrum comprising absorption peaks at3479, 3082, 2886, 1850, 1709, 1596, 1494, 1461, 1430 and 1371 cm⁻¹. 5.The compound of claim 3 further characterized by: an infra red spectrumcomprising absorption peaks at 1272, 1231, 1127 and 1070 cm⁻¹.
 6. Thecompound of claim 3 further characterized by: a Raman spectrumcomprising absorption peaks at 1177, 1015, 964, 948, 926, 905, 882, 872,833 and 767 cm⁻¹.